KR101280086B1 - Method for preparing n-phenylpyrazole-1-carboxamides - Google Patents
Method for preparing n-phenylpyrazole-1-carboxamides Download PDFInfo
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- KR101280086B1 KR101280086B1 KR20077015525A KR20077015525A KR101280086B1 KR 101280086 B1 KR101280086 B1 KR 101280086B1 KR 20077015525 A KR20077015525 A KR 20077015525A KR 20077015525 A KR20077015525 A KR 20077015525A KR 101280086 B1 KR101280086 B1 KR 101280086B1
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- KR
- South Korea
- Prior art keywords
- formula
- mixture
- compound
- mmol
- sulfonyl chloride
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 105
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 56
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims description 128
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 123
- 239000002904 solvent Substances 0.000 claims description 29
- 229910052794 bromium Inorganic materials 0.000 claims description 28
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- -1 carboxylic acid compound Chemical class 0.000 claims description 20
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 19
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 18
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical group CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 150000003512 tertiary amines Chemical group 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 150000003222 pyridines Chemical class 0.000 claims description 7
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 3
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 claims 1
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 abstract description 23
- 239000007858 starting material Substances 0.000 abstract description 11
- UQMSSNPGHUMLNM-UHFFFAOYSA-N n-phenylpyrazole-1-carboxamide Chemical compound C1=CC=NN1C(=O)NC1=CC=CC=C1 UQMSSNPGHUMLNM-UHFFFAOYSA-N 0.000 abstract description 8
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 239000007787 solid Substances 0.000 description 37
- 239000000460 chlorine Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- 239000000843 powder Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- FORBXGROTPOMEH-UHFFFAOYSA-N 5-bromo-2-(3-chloropyridin-2-yl)pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl FORBXGROTPOMEH-UHFFFAOYSA-N 0.000 description 14
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 14
- 150000002367 halogens Chemical class 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- YUENFNPLGJCNRB-UHFFFAOYSA-N anthracen-1-amine Chemical compound C1=CC=C2C=C3C(N)=CC=CC3=CC2=C1 YUENFNPLGJCNRB-UHFFFAOYSA-N 0.000 description 12
- 125000001246 bromo group Chemical group Br* 0.000 description 12
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- WOBVZGBINMTNKL-UHFFFAOYSA-N 2-amino-5-chloro-n,3-dimethylbenzamide Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1N WOBVZGBINMTNKL-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
- 238000005658 halogenation reaction Methods 0.000 description 10
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 9
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 9
- 230000026030 halogenation Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 0 CCC(C1)C(*C(C2=CC(O)=**2c(c(*)c2)ncc2P)=O)=C(*)C=C1N Chemical compound CCC(C1)C(*C(C2=CC(O)=**2c(c(*)c2)ncc2P)=O)=C(*)C=C1N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 150000002825 nitriles Chemical group 0.000 description 8
- UOCPQZOXOQZEGV-UHFFFAOYSA-N 2-amino-5-cyano-n,3-dimethylbenzamide Chemical compound CNC(=O)C1=CC(C#N)=CC(C)=C1N UOCPQZOXOQZEGV-UHFFFAOYSA-N 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- IMNDHOCGZLYMRO-UHFFFAOYSA-N n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC=C1 IMNDHOCGZLYMRO-UHFFFAOYSA-N 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- BOYQWVQNPIZDPU-UHFFFAOYSA-N methyl 2-amino-5-chloro-3-methylbenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(C)=C1N BOYQWVQNPIZDPU-UHFFFAOYSA-N 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940117389 dichlorobenzene Drugs 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000005270 trialkylamine group Chemical group 0.000 description 3
- KOPXCQUAFDWYOE-UHFFFAOYSA-N 2-amino-5-chloro-3-methylbenzoic acid Chemical compound CC1=CC(Cl)=CC(C(O)=O)=C1N KOPXCQUAFDWYOE-UHFFFAOYSA-N 0.000 description 2
- FBOWFVWOCBTBPH-UHFFFAOYSA-N 2-amino-n,3-dimethylbenzamide Chemical compound CNC(=O)C1=CC=CC(C)=C1N FBOWFVWOCBTBPH-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- AIIOWKKNDOPLNJ-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-amine Chemical compound C1=CC=C2ONC(=N)CC2=C1 AIIOWKKNDOPLNJ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000007333 cyanation reaction Methods 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- XODCNMNAVZSKOT-UHFFFAOYSA-N propanenitrile hydrate Chemical compound O.CCC#N XODCNMNAVZSKOT-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- WJUKOGPNGRUXMG-UHFFFAOYSA-N 1,2-dibromo-1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)(Br)C(Cl)(Cl)Br WJUKOGPNGRUXMG-UHFFFAOYSA-N 0.000 description 1
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- SXVRSCIZJBGJGB-UHFFFAOYSA-N 1-chloropropan-2-ylbenzene Chemical compound ClCC(C)C1=CC=CC=C1 SXVRSCIZJBGJGB-UHFFFAOYSA-N 0.000 description 1
- BKWTUCBUSLAMGU-UHFFFAOYSA-N 1-pyridin-2-ylpyrazole-3-carboxylic acid Chemical compound N1=C(C(=O)O)C=CN1C1=CC=CC=N1 BKWTUCBUSLAMGU-UHFFFAOYSA-N 0.000 description 1
- LSJVQKDTVCDSPE-UHFFFAOYSA-N 1h-pyrazole-5-sulfonamide Chemical compound NS(=O)(=O)C=1C=CNN=1 LSJVQKDTVCDSPE-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- WNAJXPYVTFYEST-UHFFFAOYSA-N 2-Amino-3-methylbenzoate Chemical compound CC1=CC=CC(C(O)=O)=C1N WNAJXPYVTFYEST-UHFFFAOYSA-N 0.000 description 1
- KGZYALLFLANLBU-UHFFFAOYSA-N 2-amino-5-bromo-n,3-dimethylbenzamide Chemical compound CNC(=O)C1=CC(Br)=CC(C)=C1N KGZYALLFLANLBU-UHFFFAOYSA-N 0.000 description 1
- 150000005749 2-halopyridines Chemical class 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- XXTPHXNBKRVYJI-UHFFFAOYSA-N 2-pyrazol-1-ylpyridine Chemical compound C1=CC=NN1C1=CC=CC=N1 XXTPHXNBKRVYJI-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- MBQXAIQVDKETLJ-UHFFFAOYSA-N 6-chloro-8-methyl-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=C1C(C)=CC(Cl)=C2 MBQXAIQVDKETLJ-UHFFFAOYSA-N 0.000 description 1
- CHKUQVBJPDLANA-UHFFFAOYSA-N 8-methyl-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=C1C(C)=CC=C2 CHKUQVBJPDLANA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- WFLRGOXPLOZUMC-UHFFFAOYSA-N [Li].O=C=O Chemical compound [Li].O=C=O WFLRGOXPLOZUMC-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- DVBUIBGJRQBEDP-UHFFFAOYSA-N cyantraniliprole Chemical compound CNC(=O)C1=CC(C#N)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl DVBUIBGJRQBEDP-UHFFFAOYSA-N 0.000 description 1
- YVKOGZPYYZLUDJ-UHFFFAOYSA-N dibromamine Chemical compound BrNBr YVKOGZPYYZLUDJ-UHFFFAOYSA-N 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 238000007350 electrophilic reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- VSFYTPXXMLJNAU-UHFFFAOYSA-N methyl 2-amino-3-methylbenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1N VSFYTPXXMLJNAU-UHFFFAOYSA-N 0.000 description 1
- NJHDBIXFFZVJGZ-UHFFFAOYSA-N methyl 3-methyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1[N+]([O-])=O NJHDBIXFFZVJGZ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- UXGJEINGLVOJME-UHFFFAOYSA-N n,n-dichloro-1,1,1-trifluoromethanamine Chemical compound FC(F)(F)N(Cl)Cl UXGJEINGLVOJME-UHFFFAOYSA-N 0.000 description 1
- 150000002816 nickel compounds Chemical class 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 238000010653 organometallic reaction Methods 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical class [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- DVLHGMFTRAFHPR-UHFFFAOYSA-N pyrazole-1-carboxamide Chemical class NC(=O)N1C=CC=N1 DVLHGMFTRAFHPR-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
화학식 2의 화합물과 화학식 3의 화합물 및 술포닐 클로라이드를 배합하여 화학식 1의 화합물을 제조하는 방법이 개시된다. 또한 이 방법을 위한 출발 물질로서 유용한 화학식 3의 화합물이 개시된다. A method of preparing a compound of formula 1 by combining a compound of formula 2 with a compound of formula 3 and sulfonyl chloride is disclosed. Also disclosed are compounds of formula 3 that are useful as starting materials for this method.
카르복실산, 안트라닐아미드, N-페닐피라졸-1-카르복사미드, 피라졸카르복실산Carboxylic acid, anthranilamide, N-phenylpyrazole-1-carboxamide, pyrazolecarboxylic acid
Description
본 발명은 카르복실산을 안트라닐아미드와 커플링시켜 N-페닐피라졸-1-카르복사미드를 제조하는 방법 및 상기 방법에 적합한 안트라닐아미드 화합물에 관한 것이다.The present invention relates to a process for coupling carboxylic acid with anthranylamide to produce N-phenylpyrazole-1-carboxamide and to anthranylamide compounds suitable for the process.
PCT 특허 공개 제WO 03/015518호에는 아르트로포디시드 (arthropodicide)로서 하기 화학식 i의 N-아실 안트라닐산 유도체의 활용이 개시되어 있다.PCT Patent Publication No. WO 03/015518 discloses the use of N-acyl anthranilic acid derivatives of formula i as arthropodicide.
상기 식 중, A 및 B는 독립적으로 O 또는 S이고, R1은 H이고, R2는 H, C1-C6 알킬, C2-C6 알콕시카르보닐 또는 C2-C6 알킬카르보닐이고, R3은 특히 H 또는 C1-C6 알킬이고, R4는 특히 H 또는 C1-C6 알킬이고, R5는 H, C1-C6 알킬 또는 할로겐이고, R6은 H, C1-C6 알킬, C1-C6 할로알킬, 할로겐, CN, C1-C4 알콕시 또는 C1-C4 할로알콕시이고, R7은 특히 페닐 고리, 벤질 고리, 5원 또는 6원의 헤테로방향족 고리, 나프틸 고리계 (고리 또는 고리계 각각은 1 내지 3개의 치환체로 임의로 치환됨)이고, R8은 특히 H이다. 이 문헌에는 화학식 i의 화합물을 제조하는 몇가지 방법이 개시되어 있다. 그러나 비용이 더 낮고, 더 효율적이고, 더 실용적이고 취급하기 더 용이한 신규 방법이 계속적으로 요구되고 있다.Wherein A and B are independently O or S, R 1 is H, R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxycarbonyl or C 2 -C 6 alkylcarbonyl R 3 is in particular H or C 1 -C 6 alkyl, R 4 is especially H or C 1 -C 6 alkyl, R 5 is H, C 1 -C 6 alkyl or halogen, R 6 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, CN, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy, R 7 is especially a phenyl ring, benzyl ring, five or six member Heteroaromatic ring, naphthyl ring system of which each ring or ring system is optionally substituted with 1 to 3 substituents, and R 8 is especially H. This document discloses several methods for preparing compounds of formula (i). However, there is a continuing need for new methods that are lower in cost, more efficient, more practical and easier to handle.
<발명의 개요>SUMMARY OF THE INVENTION [
본 발명은 하기 화학식 1의 화합물을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing the compound of formula (1).
상기 식 중,Wherein,
R1은 CH3 또는 Cl이고,R 1 is CH 3 or Cl,
R2는 Br, Cl, I 또는 CN이고, R 2 is Br, Cl, I or CN,
R3은 H 또는 C1-C4 알킬이고, R 3 is H or C 1 -C 4 alkyl,
R4는 Cl, Br, CF3, OCF2H 또는 OCH2CF3이고, R 4 is Cl, Br, CF 3 , OCF 2 H or OCH 2 CF 3 ,
R5는 F, Cl 또는 Br이고, R 5 is F, Cl or Br,
R6은 H, F 또는 Cl이고, R 6 is H, F or Cl,
Z는 CR7 또는 N이고, Z is CR 7 or N,
R7은 H, F, Cl 또는 Br이다. R 7 is H, F, Cl or Br.
상기 방법은 (1) 하기 화학식 2의 카르복실산 화합물, (2) 하기 화학식 3의 아닐린 화합물, 및 3) 술포닐 클로라이드를 배합하여 화학식 1의 화합물을 형성하는 것을 포함한다.The method includes combining (1) a carboxylic acid compound of formula (2), (2) aniline compound of formula (3), and 3) sulfonyl chloride to form a compound of formula (1).
본 발명은 또한The present invention also
R1이 CH3 또는 Cl이고, R 1 is CH 3 or Cl,
R2가 Br, Cl, I 또는 CN이고, R 2 is Br, Cl, I or CN,
R3이 H 또는 C1-C4 알킬이되,R 3 is H or C 1 -C 4 alkyl,
(a) R1 및 R2가 Cl이면, R3은 H, CH2CH3 또는 CH(CH3)CH2CH3 이외의 것이고,(a) when R 1 and R 2 are Cl, R 3 is other than H, CH 2 CH 3 or CH (CH 3 ) CH 2 CH 3 ;
(b) R1이 CH3이고 R2가 Cl, Br 또는 CN이면, R3은 CH3 또는 CH(CH3)2 이외의 것이고, (b) when R 1 is CH 3 and R 2 is Cl, Br or CN, R 3 is other than CH 3 or CH (CH 3 ) 2 ,
(c) R1이 Cl이고 R2가 Cl 또는 Br이면, R3은 CH3 또는 CH(CH3)2 이외의 것이고,(c) when R 1 is Cl and R 2 is Cl or Br, R 3 is other than CH 3 or CH (CH 3 ) 2 ,
(d) R1이 CH3이고 R2가 CN이면, R3은 H 이외의 것인(d) when R 1 is CH 3 and R 2 is CN, then R 3 is other than H;
상기 화학식 3의 아닐린 화합물에 관한 것이다.It relates to the aniline compound of formula (3).
본원에서 사용되는 바와 같이, 용어 "포함한다 (comprises, includes)" "포함하는 (comprising)", "비롯한 (including)", "갖는다 (has)", "갖는 (having)" 또는 이들의 임의의 변형은 비제한적인 포함을 망라하는 것을 의도한다. 예를 들어, 임의의 목록의 성분을 포함하는 조성물, 공정, 방법, 물품 또는 장치는 필수적으로 이들 성분 만으로 제한되는 것이 아니라, 명확하게 나열되어 있지 않거나 또는 이러한 조성물, 공정, 방법, 물품 또는 장치에 고유한 다른 성분을 포함할 수 있다. 또한, 달리 언급되지 않으면, "또는"은 포괄적인 또는의 의미이며 배타적인 또는의 의미가 아니다. 예를 들어, 조건 A 또는 B는, A가 참 (또는 존재함)이고 B가 거짓 (또는 존재하지 않음), A가 거짓 (또는 존재하지 않음)이고 B가 참 (또는 존재함), 및 A와 B 모두가 참 (또는 존재함) 중 임의의 하나에 의해 충족된다.As used herein, the terms "comprises, includes" "comprising", "including", "has", "having" or any of these Modifications are intended to encompass non-limiting inclusions. For example, a composition, process, method, article, or device comprising any list of components is not necessarily limited to these components alone, but is not explicitly listed or in such a composition, process, method, article, or device It may include other ingredients unique to it. Also, unless stated otherwise, the word "or" is meant to be inclusive or exclusive and not exclusive or meaningful. For example, a condition A or B may be a condition A or B, where A is true (or exists) and B is false (or nonexistent), A is false (or nonexistent) And B are satisfied by any one of the true (or present).
화학물질을 배합한다는 것은 화학물질을 서로 접촉시키는 것을 나타낸다.Combining chemicals refers to bringing chemicals into contact with each other.
또한, 본 발명의 원소 또는 성분 앞의 "부정 관사 (a 및 an)"는 원소 또는 성분의 경우 (즉, 출현)의 수에 관해서 제한하지 않는 것을 의도한다. 따라서, "부정관사 (a 또는 an)"는 하나 또는 하나 이상을 포함하는 것으로 이해해야 하며, 수가 명백하게 단수를 의미하지 않으면 원소 또는 성분의 단수 형태는 또한 복수를 포함한다.Also, "negative articles (a and an)" before an element or component of the present invention is not intended to be limited in terms of the number of cases (ie, appearance) of the element or component. Thus, "a" or "an" should be understood to include one or more than one, and the singular forms of elements or components also include the plural unless the number clearly means the singular.
탄소계 라디칼은 단일 결합을 통해 화학 구조의 잔기에 라디칼을 연결하는 탄소 원자를 포함하는 1가 분자 성분을 나타낸다. 탄소계 라디칼은 포화, 불포화 및 방향족 기, 사슬, 고리, 및 고리계, 및 헤테로원자를 임의로 포함할 수 있다. 탄소계 라디칼은 크기에 있어서 임의의 특정한 제한은 없지만, 본 발명과 관련하여 이들은 전형적으로 1 내지 16개의 탄소 원자 및 0 내지 3개의 헤테로원자를 포함한다. C1-C6 알킬, C1-C4 할로알킬, 및 C1-C3 알킬, 할로겐 및 니트로에서 선택된 1 내지 3개의 치환체로 임의로 치환된 페닐로 이루어진 군에서 선택된 탄소계 라디칼을 주목할 만 한다.Carbon-based radicals represent monovalent molecular components comprising carbon atoms that connect the radicals to residues of the chemical structure through a single bond. Carbon-based radicals may optionally include saturated, unsaturated and aromatic groups, chains, rings, and ring systems, and heteroatoms. Carbon-based radicals do not have any particular limitation in size, but in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. Of note is a carbon-based radical selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, and phenyl optionally substituted with 1 to 3 substituents selected from C 1 -C 3 alkyl, halogen and nitro. .
본원의 언급에서, 약어 "Ph"는 페닐을 의미한다. 알킬은 직쇄형 또는 분지형일 수 있다. 용어 자체 또는 "할로알킬"과 같은 화합물명에서 용어 "할로겐"은 불소, 염소, 브롬 또는 요오드를 포함한다. 또한, "할로알킬"과 같은 화합물명에서 사용되는 경우, 상기 알킬은 동일하거나 또는 상이할 수 있는 할로겐 원자로 부분적으로 또는 완전히 치환될 수 있다. "할로알킬"의 예는 F3C, ClCH2, CF3CH2 및 CF3CCl2를 포함한다.In the description herein, the abbreviation “Ph” means phenyl. Alkyl may be straight or branched. The term "halogen" in the term itself or in a compound name such as "haloalkyl" includes fluorine, chlorine, bromine or iodine. In addition, when used in compound names such as "haloalkyl", said alkyl may be partially or completely substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" include F 3 C, ClCH 2 , CF 3 CH 2 and CF 3 CCl 2 .
본 발명의 실시양태는 하기의 실시양태를 포함한다.Embodiments of the present invention include the following embodiments.
실시양태 M1. 화학식 2의 화합물 대 화학식 3의 화합물의 몰비가 약 1.2:1 내지 약 1:1.2인 방법.Embodiment M1. Wherein the molar ratio of compound of formula 2 to compound of formula 3 is from about 1.2: 1 to about 1: 1.2.
실시양태 M2. 실시양태 M1에 있어서, 화학식 2의 화합물 대 화학식 3의 화합물의 몰비가 약 1:1 내지 약 1:1.2인 방법. Embodiment M2. The method of embodiment M1, wherein the molar ratio of the compound of formula 2 to the compound of formula 3 is about 1: 1 to about 1: 1.2.
실시양태 M3. 실시양태 M2에 있어서, 화학식 2의 화합물 대 화학식 3의 화합물의 몰비가 약 1:1.1인 방법. Embodiment M3. The method of embodiment M2, wherein the molar ratio of the compound of formula 2 to the compound of formula 3 is about 1: 1.1.
실시양태 M4. 술포닐 클로라이드 대 화학식 2의 화합물의 몰비가 약 1:1 이상인 방법. Embodiment M4. Wherein the molar ratio of sulfonyl chloride to compound of formula 2 is at least about 1: 1.
실시양태 M5. 실시양태 M4에 있어서, 술포닐 클로라이드 대 화학식 2의 화합물의 몰비가 약 1:1 내지 약 2.5:1인 방법. Embodiment M5. The method of embodiment M4, wherein the molar ratio of sulfonyl chloride to compound of formula 2 is about 1: 1 to about 2.5: 1.
실시양태 M6. 실시양태 M5에 있어서, 술포닐 클로라이드 대 화학식 2의 화합물의 몰비가 약 1.1:1 내지 약 1.4:1인 방법. Embodiment M6. The method of embodiment M5, wherein the molar ratio of sulfonyl chloride to compound of formula 2 is about 1.1: 1 to about 1.4: 1.
실시양태 M7. 실시양태 M6에 있어서, R2가 Br, Cl 또는 I인 경우, 술포닐 클로라이드 대 화학식 2의 화합물의 몰비가 약 1.2:1인 방법. Embodiment M7. The method of embodiment M6, wherein when R 2 is Br, Cl or I, the molar ratio of sulfonyl chloride to compound of formula 2 is about 1.2: 1.
실시양태 M8. 실시양태 M6에 있어서, R2가 CN인 경우, 술포닐 클로라이드 대 화학식 2의 화합물의 몰비가 약 1.4:1인 방법. Embodiment M8. The method of embodiment M6, wherein when R 2 is CN, the molar ratio of sulfonyl chloride to compound of formula 2 is about 1.4: 1.
실시양태 M9. 술포닐 클로라이드가 하기 화학식 4인 방법.Embodiment M9. The sulfonyl chloride is a formula (4).
상기 식 중, R8은 탄소계 라디칼이다. In said formula, R <8> is a carbon type radical.
실시양태 M10. 실시양태 M9에 있어서, R8이 C1-C4 알킬, C1-C2 할로알킬, 또는 할로겐, C1-C3 알킬 및 니트로로 이루어진 군에서 선택된 1 내지 3개의 치환체로 임의로 치환된 페닐인 방법.Embodiment M10. The phenyl of embodiment M9, wherein R 8 is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, or halogen, C 1 -C 3 alkyl and nitro How to be.
실시양태 M11. 실시양태 M10에 있어서, R8이 C1-C2 알킬, CF3, 페닐 또는 4- 메틸페닐인 방법.Embodiment M11. The method of embodiment M10, wherein R 8 is C 1 -C 2 alkyl, CF 3 , phenyl or 4-methylphenyl.
실시양태 M12. 실시양태 M11에 있어서, R8이 C1-C2 알킬, 페닐 또는 4-메틸페닐인 방법. Embodiment M12. The method of embodiment M11, wherein R 8 is C 1 -C 2 alkyl, phenyl or 4-methylphenyl.
실시양태 M13. 실시양태 M12에 있어서, R8이 CH3인 방법.Embodiment M13. The method of embodiment M12, wherein R 8 is CH 3 .
실시양태 M14. 화학식 2의 카르복실산, 화학식 3의 아닐린 및 술포닐 클로라이드를 약 -70 내지 100℃의 온도에서 배합하는 방법.Embodiment M14. A method of combining carboxylic acid of formula (2), aniline of formula (3) and sulfonyl chloride at a temperature of about -70 to 100 ° C.
실시양태 M15. 실시양태 M14에 있어서, 온도가 약 -20 내지 40℃인 방법.Embodiment M15. The method of embodiment M14, wherein the temperature is about -20 to 40 ° C.
실시양태 M16. 실시양태 M15에 있어서, 온도가 약 -10 내지 20℃인 방법.Embodiment M16. The method of embodiment M15, wherein the temperature is about -10 to 20 ° C.
실시양태 M17. 화학식 2의 카르복실산을 화학식 3의 아닐린과 배합하여 혼합물을 형성하고, 이어서 상기 혼합물을 술포닐 클로라이드와 배합하는 방법.Embodiment M17. And combining the carboxylic acid of formula 2 with the aniline of formula 3 to form a mixture, and then combining the mixture with sulfonyl chloride.
실시양태 M18. 실시양태 M17에 있어서, 술포닐 클로라이드와 배합하기 전 또는 후에 염기를 혼합물과 배합하는 방법.Embodiment M18. The method of embodiment M17, wherein the base is combined with the mixture before or after combining with sulfonyl chloride.
실시양태 M19. 실시양태 M17에 있어서, 술포닐 클로라이드와 배합하기 전 또는 후에 염기를 화학식 2의 화합물 및 화학식 3의 화합물과 배합하여 혼합물을 형성하는 방법.Embodiment M19. The method of embodiment M17, wherein the base is combined with a compound of Formula 2 and a compound of Formula 3 before or after combining with sulfonyl chloride to form a mixture.
실시양태 M20. 염기를 화학식 2의 화합물과 화학식 3의 화합물 및 술포닐 클로라이드와 배합하는 방법. Embodiment M20. A method of combining a base with a compound of formula 2 and a compound of formula 3 and sulfonyl chloride.
실시양태 M21. 실시양태 M18 내지 M20 중 어느 한 실시양태에 있어서, 염기 의 양이 술포닐 클로라이드에 대해 약 2 당량 이상인 방법.Embodiment M21. The method of any one of embodiments M18 to M20, wherein the amount of base is at least about 2 equivalents to sulfonyl chloride.
실시양태 M22. 실시양태 M21에 있어서, 염기의 양이 술포닐 클로라이드에 대해 약 2.1 당량 이상인 방법. Embodiment M22. The method of embodiment M21, wherein the amount of base is at least about 2.1 equivalents to sulfonyl chloride.
실시양태 M23. 실시양태 M22에 있어서, 염기의 양이 술포닐 클로라이드에 대해 약 2.1 내지 2.2 당량인 방법. Embodiment M23. The method of embodiment M22, wherein the amount of base is about 2.1 to 2.2 equivalents relative to sulfonyl chloride.
실시양태 M24. 실시양태 M18 내지 M20 중 어느 한 실시양태에 있어서, 염기가 (임의로 치환된 피리딘을 비롯한) 3급 아민에서 선택되는 것인 방법. Embodiment M24. The method of any one of embodiments M18-M20, wherein the base is selected from tertiary amines (including optionally substituted pyridine).
실시양태 M25. 실시양태 M24에 있어서, 염기가 임의로 치환된 피리딘 및이의 혼합물에서 선택되는 것인 방법.Embodiment M25. The method of embodiment M24, wherein the base is selected from optionally substituted pyridine and mixtures thereof.
실시양태 M26. 실시양태 M25에 있어서, 염기가 2-피콜린, 3-피콜린, 2,6-루티딘, 피리딘 및 이들의 혼합물에서 선택되는 것인 방법.Embodiment M26. The method of embodiment M25, wherein the base is selected from 2-picoline, 3-picoline, 2,6-lutidine, pyridine and mixtures thereof.
실시양태 M27. 실시양태 M26에 있어서, 염기가 3-피콜린인 방법. Embodiment M27. The method of embodiment M26, wherein the base is 3-picolin.
실시양태 M28. 용매를 화학식 2의 화합물과 화학식 3의 화합물 및 술포닐 클로라이드와 배합하는 방법.Embodiment M28. A method of combining a solvent with a compound of formula 2, a compound of formula 3, and sulfonyl chloride.
실시양태 M29. 실시양태 M17에 있어서, 술포닐 클로라이드와 배합하기 전에 용매를 화학식 2의 화합물 및 화학식 3의 화합물과 배합하여 혼합물을 형성하는 방법.Embodiment M29. The method of embodiment M17, wherein the solvent is combined with the compound of formula 2 and the compound of formula 3 to form a mixture prior to combining with sulfonyl chloride.
실시양태 M30. 실시양태 M28 또는 M29에 있어서, 용매가 니트릴 (예를 들어 아세토니트릴, 프로피오니트릴), 에스테르 (예를 들어 메틸 아세테이트, 에틸 아세테이트, 부틸 아세테이트), 케톤 (예를 들어 아세톤, 메틸 에틸 케톤, 메틸 부틸 케톤, 할로알칸 (예를 들어 디클로로메탄, 트리클로로메탄), 에테르 (예를 들어 에틸 에테르, 메틸 tert-부틸 에테르, 테트라히드로푸란, p-디옥산), 방향족 탄화수소 (예를 들어 벤젠, 톨루엔, 클로로벤젠, 디클로로벤젠), 3급 아민 (예를 들어 트리알킬아민, 디알킬아닐린, 임의로 치환된 피리딘), 및 이들의 혼합물에서 선택되는 것인 방법.Embodiment M30. For embodiments M28 or M29, the solvent is nitrile (eg acetonitrile, propionitrile), ester (eg methyl acetate, ethyl acetate, butyl acetate), ketone (eg acetone, methyl ethyl ketone, methyl Butyl ketone, haloalkanes (eg dichloromethane, trichloromethane), ethers (eg ethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (eg benzene, toluene , Chlorobenzene, dichlorobenzene), tertiary amines (eg trialkylamine, dialkylaniline, optionally substituted pyridine), and mixtures thereof.
실시양태 M31. 실시양태 M30에 있어서, 용매가 3급 아민 (예를 들어, 트리알킬아민, 디알킬아닐린, 임의로 치환된 피리딘) 및 이들의 혼합물에서 선택되는 것인 방법. Embodiment M31. The method of embodiment M30, wherein the solvent is selected from tertiary amines (eg, trialkylamines, dialkylanilines, optionally substituted pyridine) and mixtures thereof.
실시양태 M32. 실시양태 M30에 있어서, 용매가 니트릴 (예를 들어, 아세토니트릴, 프로피오니트릴), 에스테르 (예를 들어, 메틸 아세테이트, 에틸 아세테이트, 부틸 아세테이트), 케톤 (예를 들어, 아세톤, 메틸 에틸 케톤, 메틸 부틸 케톤, 할로알칸 (예를 들어, 디클로로메탄, 트리클로로메탄), 에테르 (예를 들어, 에틸 에테르, 메틸 tert-부틸 에테르, 테트라히드로푸란, p-디옥산), 방향족 탄화수소 (예를 들어, 벤젠, 톨루엔, 클로로벤젠, 디클로로벤젠), 및 이들의 혼합물에서 선택되는 것인 방법.Embodiment M32. In embodiment M30, the solvent is nitrile (eg acetonitrile, propionitrile), ester (eg methyl acetate, ethyl acetate, butyl acetate), ketone (eg acetone, methyl ethyl ketone, Methyl butyl ketone, haloalkanes (eg dichloromethane, trichloromethane), ethers (eg ethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (eg , Benzene, toluene, chlorobenzene, dichlorobenzene), and mixtures thereof.
실시양태 M33. 실시양태 M32에 있어서, 용매가 아세토니트릴인 방법. Embodiment M33. The method of embodiment M32, wherein the solvent is acetonitrile.
실시양태 C1. R1이 CH3인 화학식 3의 화합물. Embodiment C1. A compound of formula 3 wherein R 1 is CH 3 .
실시양태 C2. R2가 Br 또는 Cl인 화학식 3의 화합물.Embodiment C2. A compound of formula 3, wherein R 2 is Br or Cl.
실시양태 C3. R2가 I인 화학식 3의 화합물. Embodiment C3. A compound of formula 3 wherein R 2 is I.
실시양태 C4. R2가 CN인 화학식 3의 화합물. Embodiment C4. A compound of formula 3, wherein R 2 is CN.
실시양태 C5. R3이 H 또는 CH3인 화학식 3의 화합물. Embodiment C5. A compound of formula 3 wherein R 3 is H or CH 3 .
실시양태 C6. R3이 CH3인 화학식 3의 화합물. Embodiment C6. A compound of formula 3 wherein R 3 is CH 3 .
R1이 CH3이고, R2가 Cl이고, R3이 H, CH2CH3, CH2CH2CH3, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다. 또한 R1이 CH3이고, R2가 Br이고, R3이 H, CH2CH3, CH2CH2CH3, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다. 또한 R1이 CH3이고, R2가 I이고, R3이 H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다. 또한 R1이 CH3이고, R2가 CN이고, R3이 CH2CH3, CH2CH2CH3, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)인 화학식 3의 화합물을 주목할 만하다. 또한 R1이 Cl이고, R2가 Cl이고, R3이 CH2CH2CH3, CH2CH2CH2CH3, CH2CH(CH3)2 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다. R1이 Cl이고, R2가 Br이고, R3이 H, CH2CH3, CH2CH2CH3, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다. R1이 Cl이고, R2가 I이고, R3이 H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다. R1이 Cl이고, R2가 CN이고, R3이 H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3 또는 C(CH3)3인 화학식 3의 화합물을 주목할 만하다.R 1 is CH 3 , R 2 is Cl, R 3 is H, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH ( Of note is the compound of formula 3, which is CH 3 ) CH 2 CH 3 or C (CH 3 ) 3 . R 1 is CH 3 , R 2 is Br, R 3 is H, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH Of note is a compound of formula 3, wherein (CH 3 ) CH 2 CH 3 or C (CH 3 ) 3 . R 1 is CH 3 , R 2 is I, R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , Of note is the compound of formula 3, which is CH 2 CH (CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 or C (CH 3 ) 3 . R 1 is CH 3 , R 2 is CN, R 3 is CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH (CH Of note is a compound of formula 3, which is 3 ) CH 2 CH 3 or C (CH 3 ). In addition, and R 1 is Cl, and R 2 is Cl, R 3 is CH 2 CH 2 CH 3, CH 2 CH 2 CH 2 CH 3, CH 2 CH (CH 3) 2 or C (CH 3) 3 of formula (3) Of note is the compound. R 1 is Cl, R 2 is Br, R 3 is H, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH (CH Of note is a compound of formula 3, which is 3 ) CH 2 CH 3 or C (CH 3 ) 3 . R 1 is Cl, R 2 is I, R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 Of note is the compound of formula 3, which is CH (CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 or C (CH 3 ) 3 . R 1 is Cl, R 2 is CN, R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 Of note is the compound of formula 3, which is CH (CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 or C (CH 3 ) 3 .
하기 반응식에서, 달리 지시되지 않으면 하기 화학식 1의 화합물 내지 화학식 34의 화합물에서 R1, R2, R3, R4, R5 및 R6의 정의는 발명의 개요 및 실시양태의 설명에서 정의된 바와 같다.In the following schemes, unless otherwise indicated, the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 in compounds of Formula 1 to compounds of Formula 34 are defined in the Summary of the Invention and Description of Embodiments. As shown.
반응식 1에서 나타낸 바와 같이, 본 발명은, 전형적으로는 염기 및 용매의 존재하에서, 술포닐 클로라이드를 사용하여 화학식 2의 카르복실산을 화학식 3의 안트라닐아미드와 커플링시켜 화학식 1의 화합물을 제조하는 방법에 관한 것이다.As shown in Scheme 1, the present invention typically provides a compound of Formula 1 by coupling a carboxylic acid of Formula 2 with anthranylamide of Formula 3 using sulfonyl chloride in the presence of a base and a solvent. It is about how to.
따라서, 본 발명의 방법에서 화학식 2의 피라졸카르복실산, 화학식 3의 아닐린 및 술포닐 클로라이드를 배합하여 (즉, 접촉시켜) 상응하는 화학식 1의 N-페닐-피라졸-1-카르복사미드를 제공한다.Thus, in the process of the invention, the pyrazolecarboxylic acid of formula (2), aniline of formula (3) and sulfonyl chloride are combined (ie contacted) to correspond to the corresponding N-phenyl-pyrazole-1-carboxamide of formula (1). To provide.
다양한 범위의 반응물 비가 가능하지만, 화학식 3의 화합물 대 화학식 2의 화합물의 공칭 몰비는 전형적으로는 약 0.9 내지 1.1이고, 모든 화합물이 완전히 소모될 수 있도록 약 1.0이 바람직하다. 본 발명의 방법은 다양한 범위의 온도에 걸쳐서 수행할 수 있지만, 통상적으로는 -70℃ 내지 +100℃의 온도 범위에서 수행한다. -20℃ 내지 +40℃의 온도를 주목할 만하다. 편리한 작동, 유리한 반응 속도 및 선택성, 및 높은 공정 수율의 이유로 -10℃ 내지 +20℃의 온도를 특히 주목할 만하다.While a wide range of reactant ratios is possible, the nominal molar ratio of the compound of Formula 3 to the compound of Formula 2 is typically about 0.9 to 1.1, with about 1.0 being preferred so that all compounds can be consumed completely. The process of the present invention can be carried out over a wide range of temperatures, but is typically carried out in a temperature range of -70 ° C to + 100 ° C. Of note is a temperature of -20 ° C to + 40 ° C. Of particular note is a temperature of -10 ° C to + 20 ° C for reasons of convenient operation, advantageous reaction speed and selectivity, and high process yield.
카르복실산과 안트라닐아미드의 커플링을 용이하게 하기 위해서 술포닐 클로라이드 화합물을 반응물로서 사용하여 N-페닐피라졸-1-카르복사미드를 형성한다. 술포닐 클로라이드 대 화학식 2의 화합물의 공칭 몰비는 전형적으로는 약 1.0 내지 2.5이고, 하기에 기재된 고리화 부반응이 소량 (즉, 0 내지 10%)을 넘지않게 발생하게 하는 경우에는 바람직하게는 약 1.1 내지 1.4이다. 술포닐 클로라이드는 일 반적으로는 화학식 R8S(O)2Cl (화학식 4) (여기서, R8은 탄소계 라디칼임)이다. 본 발명을 위해서 전형적으로 R8은 C1-C4 알킬, C1-C2 할로알킬, 또는 할로겐, C1-C3 알킬 및 니트로로 이루어진 군에서 선택된 1 내지 3개의 치환체로 임의로 치환된 페닐이다. 시판되기 때문에 본 발명을 위해서 바람직한 술포닐 클로라이드 화합물은 메탄술포닐 클로라이드 (R8이 CH3임), 프로판술포닐 클로라이드 (R8이 (CH2)2CH3임), 벤젠술포닐 클로라이드 (R8이 Ph임), 및 및 p-톨루엔술포닐 클로라이드 (R8이 4-CH3-Ph임)를 포함한다. 더 가격이 싸고/싸거나 첨가가 용이하고/용이하거나 폐기물이 적은 이유 때문에 메탄술포닐 클로라이드이 보다 바람직하다.In order to facilitate coupling of the carboxylic acid and anthranylamide, sulfonyl chloride compounds are used as reactants to form N-phenylpyrazole-1-carboxamide. The nominal molar ratio of sulfonyl chloride to compound of formula (2) is typically from about 1.0 to 2.5, preferably about 1.1 if the cyclization side reaction described below occurs no greater than a small amount (i.e. 0 to 10%). To 1.4. Sulfonyl chloride is typically of the formula R 8 S (O) 2 Cl (Formula 4), wherein R 8 is a carbon-based radical. For the purposes of the present invention typically R 8 is C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, or phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl and nitro to be. Since commercially available sulfonyl chloride compounds for the present invention include methanesulfonyl chloride (R 8 is CH 3 ), propanesulfonyl chloride (R 8 is (CH 2 ) 2 CH 3 ), benzenesulfonyl chloride (R 8 is Ph), and p-toluenesulfonyl chloride (R 8 is 4-CH 3 -Ph). Methanesulfonyl chloride is more preferred because it is cheaper and / or easier to add and / or easier to waste.
본 발명의 방법에서, 술포닐 클로라이드를 화학식 2의 피라졸카르복실산 및 화학식 3의 아닐린과 배합한다. 다양한 순서, 예를 들어 술포닐 클로라이드를 화학식 2의 카르복실산과 배합하여 혼합물을 형성하고 이어서 상기 혼합물을 화학식 3의 아닐린과 배합하는 순서로 반응물을 배합할 수 있다. 그러나, 특정 화학식 1의 N-페닐피라졸-1-카르복사미드를 제조하기 위해서, 가장 바람직한 배합 순서는 화학식 2의 카르복실산을 화학식 3의 아닐린과 배합하여 혼합물을 형성하고 이어서 술포닐 클로라이드를 상기 혼합물과 배합하는 것 (예를 들어, 화학식 2의 화합물과 화학식 3의 화합물의 혼합물에 술포닐 클로라이드를 첨가하는 것)을 포함하는 것이라는 것을 발견하였고, 그 이유는 이러한 첨가 순서가 커플링 방법의 편리한 제어 를 가능하게 하기 때문이다. 술포닐 클로라이드 화합물의 첨가 속도를 간단히 제어함으로써 반응 속도를 쉽게 제어할 수 있다. 따라서 주목할 만한 본 발명의 방법의 실시양태는 (1) 화학식 2의 카르복실산과 화학식 3의 아닐린을 배합하여 혼합물을 형성하고, (2) 이어서 상기 혼합물을 술포닐 클로라이드와 배합하는 순차적인 단계를 포함한다. 화학식 2의 아닐린을 함유하는 혼합물에 술포닐 클로라이드를 첨가하는 것은 바람직하지 않은 부반응을 잠재적으로 일으킬 수 있지만, 화학식 2의 화합물 및 화학식 3의 화합물의 특정 입체전자 프로파일이 본 발명의 방법을 사용하여 현저하게 높은 수율로 화학식 1의 화합물을 수득하는 것을 용이하게 한다는 것을 발견하였다.In the process of the invention, sulfonyl chloride is combined with pyrazolecarboxylic acid of formula (2) and aniline of formula (3). The reactants may be combined in various orders, for example, sulfonyl chloride with the carboxylic acid of Formula 2 to form a mixture, and then in combination with the aniline of Formula 3. However, in order to prepare certain N-phenylpyrazole-1-carboxamides of formula (1), the most preferred formulation sequence is to combine the carboxylic acid of formula (2) with aniline of formula (3) to form a mixture, followed by sulfonyl chloride It was found that compounding with the mixture includes, for example, adding sulfonyl chloride to a mixture of a compound of formula 2 and a compound of formula 3, because this order of addition This is because it enables convenient control. The reaction rate can be easily controlled by simply controlling the addition rate of the sulfonyl chloride compound. A notable embodiment of the inventive process thus comprises (1) combining the carboxylic acid of formula (2) with aniline of formula (3) to form a mixture, and (2) subsequently combining the mixture with sulfonyl chloride. do. The addition of sulfonyl chloride to a mixture containing aniline of formula (2) can potentially cause undesirable side reactions, but certain stereoelectron profiles of compounds of formula (2) and compounds of formula (3) are significant using the method of the present invention. It was found to facilitate the obtaining of the compound of formula 1 in a high yield.
화학식 2의 출발 화합물과 화학식 3의 출발 화합물 및 술포닐 클로라이드를 이들 각각이 적어도 부분적으로 용해성인 배합된 액상 중에서 서로 접촉시킬 때 화학식 1의 화합물이 형성된다. 특별하게 화학식 2의 출발 물질 및 화학식 3의 출발 물질은 전형적으로는 통상의 주변 온도에서 고형물이기 때문에, 상기 방법은 가장 만족스럽게는 출발 화합물이 상당히 용해성인 용매를 사용하여 수행한다. 따라서 전형적으로 상기 방법은 용매를 포함하는 액상에서 수행한다. 일부 경우에서 화학식 2의 카르복실산은 단지 약간 용해성일 수 있지만, 첨가된 염기와의 상기 카르복실산의 염이 용매 중에서 보다 용해성일 수 있다. 이 방법을 위해서 적합한 용매는 니트릴, 예를 들어 아세토니트릴 및 프로피오니트릴, 에스테르, 예를 들어 메틸 아세테이트, 에틸 아세테이트, 및 부틸 아세테이트, 케톤, 예를 들어 아세톤, 메틸 에틸 케톤 (MEK), 및 메틸 부틸 케톤, 할로알칸, 예를 들어 디클로로메탄 및 트리 클로로메탄, 에테르, 예를 들어 에틸 에테르, 메틸 tert-부틸 에테르, 테트라히드로푸란 (THF), 및 p-디옥산, 방향족 탄화수소, 예를 들어 벤젠, 톨루엔, 클로로벤젠, 및 디클로로벤젠, 3급 아민, 예를 들어 트리알킬아민, 디알킬아닐린, 및 임의로 치환된 피리딘, 및 이들의 혼합물을 포함한다. 주목할 만한 용매는 아세토니트릴, 프로피오니트릴, 에틸 아세테이트, 아세톤, MEK, 디클로로메탄, 메틸 tert-부틸 에테르, THF, p-디옥산, 톨루엔, 및 클로로벤젠을 포함한다. 아세토니트릴은 대개 수율 및/또는 순도가 우수하게 생성물을 제공하기 때문에 용매로서 특히 주목할 만하다.Compounds of formula 1 are formed when the starting compounds of formula 2 and starting compounds of formula 3 and sulfonyl chlorides are contacted with each other in a combined liquid phase, each of which is at least partially soluble. In particular, since the starting material of formula (2) and the starting material of formula (3) are typically solids at normal ambient temperatures, the process is most satisfactorily carried out using solvents in which the starting compounds are highly soluble. Thus typically the process is carried out in a liquid phase comprising a solvent. In some cases the carboxylic acid of formula (2) may be only slightly soluble, but salts of the carboxylic acid with added base may be more soluble in the solvent. Suitable solvents for this method include nitriles such as acetonitrile and propionitrile, esters such as methyl acetate, ethyl acetate, and butyl acetate, ketones such as acetone, methyl ethyl ketone (MEK), and methyl Butyl ketones, haloalkanes such as dichloromethane and trichloromethane, ethers such as ethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), and p-dioxane, aromatic hydrocarbons such as benzene , Toluene, chlorobenzene, and dichlorobenzene, tertiary amines such as trialkylamine, dialkylaniline, and optionally substituted pyridine, and mixtures thereof. Notable solvents include acetonitrile, propionitrile, ethyl acetate, acetone, MEK, dichloromethane, methyl tert-butyl ether, THF, p-dioxane, toluene, and chlorobenzene. Acetonitrile is particularly notable as a solvent because it usually gives a good product in yield and / or purity.
본 발명의 방법의 반응은 부산물로서 염화수소를 생성하고 이것은 화학식 1, 2 및 3의 화합물 내의 염기성 중심에 결합하기 때문에, 상기 방법은 가장 만족스럽게는 적어도 1종의 첨가된 염기의 존재하에서 수행한다. 염기는 또한 술포닐 클로라이드 화합물 및 안트라닐아미드와 카르복실산의 구조적인 상호작용을 용이하게 할 수 있다. 첨가된 염기와 화학식 2의 카르복실산의 반응은 염을 형성하고, 이것은 반응 매질 중에서 카르복실산보다 용해성이 더 클 수 있다. 염기는 술포닐 클로라이드의 첨가와 동시에, 차례로, 또는 직후에 첨가할 수 있지만 염기는 전형적으로는 술포닐 클로라이드의 첨가 전에 첨가한다. 일부 용매, 예를 들어 3급 아민은 또한 염기로서 작용하고, 이것을 용매로서 사용하는 경우 이것은 염기로서의 화학량론적인 양보다 훨씬 과량으로 존재할 것이다. 염기를 용매로서 사용하지 않는 경우, 충전된 염기 대 충전된 술포닐 클로라이드의 공칭 몰비는 전형적으로는 약 2.0 내지 2.2이고, 바람직하게는 약 2.1 내지 2.2이다. 바람직한 염기는 치환된 피리딘을 비롯한 3급 아민이다. 보다 바람직한 염기는 2-피콜린, 3-피콜린, 2,6-루티딘, 및 피리딘을 포함한다. 화학식 2의 카르복실산과 3-피콜린의 염이 대개 아세토니트릴과 같은 용매 중에서 고도로 용해성이기 때문에 3-피콜린을 염기로서 특히 주목할 만하다.The reaction is most satisfactorily carried out in the presence of at least one added base since the reaction of the process of the invention produces hydrogen chloride as a by-product and which binds to the basic center in the compounds of formulas (1), (2) and (3). The base may also facilitate the structural interaction of the sulfonyl chloride compound and anthranylamide with the carboxylic acid. The reaction of the added base with the carboxylic acid of formula (2) forms a salt, which may be more soluble than the carboxylic acid in the reaction medium. Bases can be added simultaneously, in turn, or immediately after the addition of sulfonyl chloride, but the base is typically added before the addition of sulfonyl chloride. Some solvents, for example tertiary amines, also act as bases and when used as solvents they will be present in much excess than stoichiometric amounts as bases. If no base is used as solvent, the nominal molar ratio of charged base to charged sulfonyl chloride is typically about 2.0 to 2.2, preferably about 2.1 to 2.2. Preferred bases are tertiary amines including substituted pyridine. More preferred bases include 2-picoline, 3-picoline, 2,6-lutidine, and pyridine. 3-picoline is particularly notable as a base because the salts of carboxylic acid of formula 2 and 3-picolin are usually highly soluble in a solvent such as acetonitrile.
본 발명의 방법의 특징은 N-페닐피라졸-1-카르복사미드를 형성하는 동안 소모되는 카르복실산, 술포닐 클로라이드 및 안트라닐아미드의 양을 제한하고 폐기물을 감소시키면서 화학식 1의 N-페닐피라졸-1-카르복사미드가 효율적으로 생성되게 한다. 본 발명의 방법은 커플링 방법을 편리하게 제어하고 화학식 1과 같은 N-페닐피라졸-1-카르복사미드의 제조를 위해 이미 공지된 방법에 비해 보다 단계가 적고 공정이 간단한 방법을 제공한다.A feature of the process of the present invention is that the N-phenyl of formula 1 is limited while limiting the amount of carboxylic acid, sulfonyl chloride and anthranylamide consumed during the formation of N-phenylpyrazole-1-carboxamide. Allows pyrazole-1-carboxamides to be produced efficiently. The method of the present invention provides a method with less steps and a simpler process than the known methods for the convenient control of the coupling method and for the preparation of N-phenylpyrazole-1-carboxamides such as formula (1).
본 발명의 바람직한 실시양태는 화학식 2의 피라졸카르복실산, 화학식 3의 안트라닐산, 및 적합한 염기를 적합한 용매 중에서 배합하고, 그 후 (단독으로 또는 적합한 용매와 혼합하여) 술포닐 클로라이드 화합물을 첨가하는 것이다.Preferred embodiments of the present invention combine the pyrazolecarboxylic acid of formula (2), anthranilic acid of formula (3), and a suitable base in a suitable solvent, followed by addition of a sulfonyl chloride compound (alone or in combination with a suitable solvent). It is.
화학식 1의 N-페닐피라졸-1-카르복사미드 생성물은 결정화, 여과 및 추출을 비롯한 당업자에게 공지된 방법에 의해 반응 혼합물에서 분리할 수 있다. 반응식 2에 나타낸 바와 같이, 일부 경우에 커플링 반응 조건 하에서 아미드 1이 화학식 시클로-1의 이미노벤족사진으로 부분적으로 고리화된다.The N-phenylpyrazole-1-carboxamide product of Formula 1 may be separated from the reaction mixture by methods known to those skilled in the art, including crystallization, filtration and extraction. As shown in Scheme 2, in some cases amide 1 is partially cyclized to the iminobenzoxazine of the formula cyclo-1 under coupling reaction conditions.
이 경우에, 반응 생성물을 분리하기 전에 화학식 시클로-1의 화합물을 화학식 1의 아미드로 다시 전환시키는 것이 종종 유리하다. 이러한 전환은 반응 혼합물을 수성산으로 처리함으로써 성취될 수 있다. 별법으로, 화학식 시클로-1의 이미노벤족사진과 화학식 1의 아미드의 혼합물을 단리한 후, 임의로는 적합한 유기 용매의 존재하에서, 예를 들어 묽은 수성산으로 처리함으로써 이 혼합물을 화학식 1의 아미드로 전환할 수 있다.In this case, it is often advantageous to convert the compound of formula cyclo-1 back to the amide of formula 1 before separating the reaction product. This conversion can be accomplished by treating the reaction mixture with aqueous acid. Alternatively, the mixture of the iminobenzoxazine of formula (cyclo-1) and the amide of formula (1) is isolated and then treated with an amide of formula (1), for example by treatment with dilute aqueous acid, in the presence of a suitable organic solvent. You can switch.
이 방법의 바람직한 조건 하에서, 화학식 1의 목적 생성물을 화학식 시클로-1의 화합물로 전환시키는 고리화 부반응은 일반적으로 단지 소량으로 일어나며, 일어나더라도 이 경우 술포닐 클로라이드와 염기의 바람직한 비는 커플링 반응을 완결시키기에 충분하다. 그러나, 일부 화학식 2의 피라졸카르복실산, 화학식 3의 안트라닐산 (예를 들어 R2가 CN인 경우) 및 반응 조건 (예를 들어, 염기로서 2,6-루티딘과 같은 입체 장애형 치환된 피리딘을 사용하는 경우)의 경우에, 화학식 1의 목적 생성물의 화학식 시클로-1 화합물로의 전환은 보다 상당한 양으로 발생할 수 있거나 또는 우세한 반응일 수 있다. 이러한 경우, 술포닐 클로라이드 및 염기를 높 은 비율로 사용하는 것이 커플링 반응의 완결을 용이하게 할 수 있다. 고리화 부반응은 커플링 반응에서 소모되는 술포닐 클로라이드의 당량 이외에 술포닐 클로라이드의 당량을 화학량론적으로 소모한다. 따라서, 100% 고리화를 발생시키려면, 출발 물질의 완전한 소모를 성취하기 위해서 술포닐 클로라이드 대 화학식 2의 화합물의 몰비가 2:1인 것이 화학량론적으로 필요하고, 전형적으로는 몰비가 약 2.5:1 이하인 술포닐 클로라이드 대 화학식 2의 화합물을 사용하고, 이에 비해 고리화가 단지 5 내지 10% (R2가 CN인 경우 대부분의 염기의 사용에서 전형적임)인 정도로 발생하는 경우에는 몰비가 약 1.4:1인 술포닐 클로라이드 대 화학식 2의 화합물을 사용하고, 고리화 부반응이 무시될 정도 (R2가 Br, Cl 또는 I인 경우 대부분의 염기의 사용에서 전형적임)로 발생하는 경우에는 몰비가 약 1.2:1인 술포닐 클로라이드 대 화학식 2의 화합물을 사용한다. 고리화 반응이 발생하는 것이 관찰되면 술포닐 클로라이드 및 염기의 추가량을 반응이 진행되는 동안 첨가할 수 있다.Under the preferred conditions of this process, cyclization side reactions which convert the desired product of formula (1) to a compound of formula (cyclo-1) generally occur only in small amounts, in which case the preferred ratio of sulfonyl chloride and base is such that It is enough to complete. However, some pyrazolecarboxylic acids of Formula 2, anthranilic acid of Formula 3 (eg when R 2 is CN) and reaction conditions (eg, sterically hindered substitutions such as 2,6-lutidine as base) In the case of using pyridine), the conversion of the desired product of formula 1 to the formula cyclo-1 compound may occur in a greater amount or may be a dominant reaction. In such cases, the use of sulfonyl chloride and base in high proportions may facilitate the completion of the coupling reaction. Cyclic side reactions stoichiometrically consume an equivalent of sulfonyl chloride in addition to the equivalent of sulfonyl chloride consumed in the coupling reaction. Thus, to generate 100% cyclization, it is stoichiometrically required that the molar ratio of sulfonyl chloride to the compound of formula 2 is 2: 1 in order to achieve complete consumption of the starting material, and typically the molar ratio is about 2.5: A molar ratio of about 1.4: is used when using sulfonyl chloride of less than 1 to a compound of formula (2), in comparison to which cyclization occurs at only 5-10% (typical for most bases when R 2 is CN). A molar ratio of about 1.2 is used when sulfonyl chloride of 1 to the compound of formula 2 occurs and occurs to the extent that cyclization side reactions are neglected (typical for most bases where R 2 is Br, Cl or I). Sulfonyl chloride is used as the compound of formula (2). If a cyclization reaction is observed, additional amounts of sulfonyl chloride and base can be added during the reaction.
상기는 전환을 완결하기 위해 필요한 만큼 공정의 임의의 성분의 추가량을 어느 시간에나 첨가할 수 있는, 본 발명의 방법의 가치있는 특징을 설명한다. 가치있는 이러한 특징의 다른 예는 화학식 2의 성분 또는 화학식 3의 성분을 반응 혼합물에 부주의하게 불충분하게 충전시켰을 상황과 관련된다. 이러한 불충분 충전은 HPLC 및 NMR을 비롯한 일반적으로 공지되고 이용가능한 임의의 다양한 방법을 사용하여 반응 혼합물을 분석함으로써 감지할 수 있다. 이것이 감지되면, 반응 혼합물에 적절한 성분을 더 첨가함으로써 불충분 충전을 수정할 수 있다. 이것은 충 전 오류를 회복시켜주고 발생할 수도 있는 값비싼 중간체의 생성 폐기물을 방지하기 때문에 큰 규모의 작업에 특히 유용할 수 있다.The above describes the valuable features of the process of the invention, which can add at any time an additional amount of any component of the process as needed to complete the conversion. Another example of this valuable feature relates to the situation in which components of formula (2) or components of formula (3) have been inadvertently inadequately charged to the reaction mixture. Such insufficient filling can be detected by analyzing the reaction mixture using any of a variety of commonly known and available methods, including HPLC and NMR. If this is detected, insufficient filling can be corrected by adding more suitable ingredients to the reaction mixture. This can be particularly useful for large scale operations because it recovers from charging errors and prevents the production of expensive intermediates that may occur.
화학식 2의 피라졸카르복실산은 문헌 [Rodd's Chemistry of Chemistry of Carbon Compounds, Vol. IVa to IVl, S. Coffey editor, Elsevier Scientific Publishing, New York, 1973], [Comprehensive Heterocyclic Chemistry, Vol. 1-7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984], [Comprehensive Heterocyclic Chemistry II, Vol. 1-9, A. R. Katritzky, C. W. Rees, and E. F. Scriven editors, Pergamon Press, New York, 1996], 및 연속 간행물인 [The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York]을 비롯한 문헌에서 공지된 헤테로시클릭 합성 방법을 사용하여 제조할 수 있다. (피라졸카르복실산을 비롯한) 다양한 헤테로시클릭산 및 이들의 합성을 위한 일반적인 방법은 PCT 특허 공개 제WO 98/57397호에서 발견된다.Pyrazolecarboxylic acids of Formula 2 are described in Rodd's Chemistry of Chemistry of Carbon Compounds, Vol. IVa to IVl, S. Coffey editor, Elsevier Scientific Publishing, New York, 1973, Comprehensive Heterocyclic Chemistry, Vol. 1-7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984, Comprehensive Heterocyclic Chemistry II, Vol. 1-9, AR Katritzky, CW Rees, and EF Scriven editors, Pergamon Press, New York, 1996, and serial publications The Chemistry of Heterocyclic Compounds, EC Taylor, editor, Wiley, New York. Prepared by using a heterocyclic synthesis method. Various heterocyclic acids (including pyrazolecarboxylic acids) and general methods for their synthesis are found in PCT Patent Publication No. WO 98/57397.
화학식 2a의 피라졸카르복실산을 제조하기에 특히 유용한 한 절차를 하기 반응식 3에 나타내었다.One procedure particularly useful for preparing pyrazolecarboxylic acids of Formula 2a is shown in Scheme 3 below.
화학식 6의 피라졸과 화학식 7의 2-할로피리딘의 반응은 목적하는 위치화학 에 대한 특이성이 양호한 화학식 8의 1-피리디닐피라졸을 양호한 수율로 산출한다. 화학식 8의 화합물을 리튬 디이소프로필아미드 (LDA)로 금속화하고 그 후 리튬염을 이산화탄소로 켄칭함으로써 화학식 2a의 1-(2-피리디닐)피라졸카르복실산을 산출한다. 이러한 방법의 주요 참고문헌으로서 PCT 특허 공개 제WO 03/015519호를 참조하기 바란다.The reaction of pyrazole of formula 6 with 2-halopyridine of formula 7 yields in good yield 1-pyridinylpyrazole of formula 8 with good specificity for the desired positional chemistry. The compound of formula 8 is metallized with lithium diisopropylamide (LDA) and then quenched with lithium carbon dioxide to yield the 1- (2-pyridinyl) pyrazolecarboxylic acid of formula 2a. See PCT Patent Publication No. WO 03/015519 as the main reference for this method.
하기 반응식 4에 나타낸 바와 같이, 화학식 9의 적절하게 치환된 이미노할라이드를 화학식 10의 치환된 프로피올레이트 또는 화학식 11의 아크릴레이트와 3+2 시클로첨가반응시켜 화학식 2b의 피라졸카르복실산을 제조할 수 있다.As shown in Scheme 4, a 3 + 2 cycloaddition of an appropriately substituted iminohalide of Formula 9 with a substituted propiolate of Formula 10 or an acrylate of Formula 11 to form a pyrazolecarboxylic acid of Formula 2b It can manufacture.
아크릴레이트와의 시클로첨가반응은 중간체 피라졸린의 피라졸로의 추가 산화가 필요하다. 화학식 12의 에스테르의 가수분해는 화학식 2b의 피라졸카르복실 산을 산출한다. 이 반응을 위해서 바람직한 이미노할라이드는 화학식 9a의 트리플루오로메틸 이미노클로라이드 및 화학식 9b의 이미노디브로마이드를 포함한다. 화학식 9a와 같은 화합물은 문헌 [J. Heterocycl. Chem. 1985, 22(2), 565-8)]에 공지되어 있다. 화학식 9b와 같은 화학식 9의 다른 화합물은 공지된 방법 (문헌 [Tetrahedron Letters 1999, 40, 2605])에 의해 수득가능하다.Cycloaddition with acrylates requires further oxidation of the intermediate pyrazoline to pyrazole. Hydrolysis of the ester of formula 12 yields a pyrazolecarboxylic acid of formula 2b. Preferred iminohalides for this reaction include trifluoromethyl iminochloride of formula 9a and iminodibromide of formula 9b. Compounds such as Formula 9a are described in J. Heterocycl. Chem. 1985, 22 (2), 565-8). Other compounds of formula 9, such as formula 9b, are obtainable by known methods (Tetrahedron Letters 1999, 40, 2605).
화학식 2b의 피라졸카르복실산을 제조하는 다른 방법을 반응식 하기 5에 나타내었다.Another method for preparing the pyrazolecarboxylic acid of Formula 2b is shown in Scheme 5 below.
화학식 13의 피라졸을 문헌 [Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729]에 기록된 바와 같은 방법을 사용하여 아릴 요오드와, 또는 문헌 [P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944]에 기록된 바와 같은 방법을 사용하여 아릴 보론산과 축합할 수 있다. 화학식 15의 생성된 부가물을 과망간산칼륨과 같은 산화제로 산화시켜 화학식 2b의 피라졸카르복실산을 산출할 수 있다.Pyrazoles of formula 13 are described in Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729 using aryl iodine, or methods described in [P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944 can be used to condense with aryl boronic acid using the method as described. The resulting adduct of formula 15 can be oxidized with an oxidizing agent such as potassium permanganate to yield the pyrazolecarboxylic acid of formula 2b.
화학식 6 및 화학식 13의 출발 피라졸은 공지 화합물이거나 또는 공지된 방법에 따라 제조할 수 있다. 예를 들어 화학식 6a의 피라졸 (R4가 CF3인 화학식 6의 화합물)은 문헌 절차에 의해 제조할 수 있다 (문헌 [J. Fluorine Chem. 1991, 55(1), 61-70]). 화학식 6b의 피라졸 (R4가 Cl 또는 Br인 화학식 6의 화합물)은 문헌 [Chem. Ber. 1966, 99(10), 3350-7]에 기재된 절차에 의해 제조할 수 있다.Starting pyrazoles of formulas (6) and (13) are known compounds or can be prepared according to known methods. For example, pyrazoles of formula 6a (compounds of formula 6 wherein R 4 is CF 3 ) can be prepared by literature procedures (J. Fluorine Chem. 1991, 55 (1), 61-70). Pyrazoles of formula 6b (compounds of formula 6 wherein R 4 is Cl or Br) are described in Chem. Ber. 1966, 99 (10), 3350-7.
화학식 6b의 화합물을 제조하기 위한 유용한 대안의 방법을 하기 반응식 6에 도시하였다.A useful alternative method for preparing the compound of formula 6b is shown in Scheme 6 below.
화학식 16의 술파모일피라졸을 n-부틸리튬으로 금속화한 후 음이온을 헥사클로로에탄 (R4가 Cl인 경우) 또는 1,2-디브로모테트라클로로에탄 (R4가 Br인 경우)으로 직접 할로겐화시켜 화학식 17a의 할로겐화 유도체를 산출한다. 실온에서 트리플루오로아세트산 (TFA)으로 술파모일기의 제거를 깨끗하게 진행시켜 양호한 수율로 화학식 6c의 피라졸을 산출한다. 당업자는 화학식 6c의 화합물이 화학식 6b의 화합물의 토토머인 것을 인식할 것이다.The sulfamoylpyrazole of formula (16) is metalized with n-butyllithium followed by anion to hexachloroethane (if R 4 is Cl) or 1,2-dibromotetrachloroethane (if R 4 is Br) Direct halogenation yields a halogenated derivative of Formula 17a. Clear removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature yields pyrazole of formula 6c in good yield. Those skilled in the art will recognize that the compound of formula 6c is a tautomer of the compound of formula 6b.
또한 하기 반응식 7에 나타낸 바와 같이 화학식 18의 피라졸린을 산화시켜 화학식 19의 피라졸을 얻고 그 후 카르복실산으로 가수분해하여 피라졸카르복실산 2를 제조할 수 있다.In addition, pyrazole carboxylic acid 2 may be prepared by oxidizing pyrazoline of formula 18 to obtain pyrazole of formula 19, and then hydrolyzing with carboxylic acid as shown in Scheme 7 below.
산화제는 과산화수소, 유기 과산화물, 과황산칼륨, 과황산나트륨, 과황산암모늄, 칼륨 모노퍼술페이트 (예를 들어, 옥손? (Oxone?), 또는 과망간산칼륨일 수 있다. 이러한 산화 반응은 용매, 바람직하게는 에테르, 예를 들어 테트라히드로푸란, 및 p-디옥산 등, 유기 에스테르, 예를 들어 에틸 아세테이트, 및 디메틸 카르보네이트 등, 또는 극성 비양자성 유기물, 예를 들어 N,N-디메틸포름아미드, 및 아세토니트릴 등의 존재하에서 수행할 수 있다.The oxidizing agent may be hydrogen peroxide, organic peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (eg Oxone®), or potassium permanganate. This oxidation reaction is a solvent, preferably Ethers such as tetrahydrofuran, and p-dioxane and the like, organic esters such as ethyl acetate, and dimethyl carbonate and the like, or polar aprotic organics such as N, N-dimethylformamide, and It may be carried out in the presence of acetonitrile and the like.
R4가 Cl 또는 Br인 화학식 18의 할로피라졸린은 하기 반응식 8에 나타낸 바와 같이 적절한 할로겐화 시약으로의 처리에 의해서 화학식 20의 피라졸론으로부터 제조할 수 있다.Halopyrazoline of formula (18) wherein R 4 is Cl or Br can be prepared from pyrazolone of formula (20) by treatment with a suitable halogenation reagent as shown in Scheme 8 below.
사용할 수 있는 할로겐화 시약은 인 옥시할라이드, 인 트리할라이드, 인 펜타할라이드, 티오닐 클로라이드, 디할로트리알킬포스포란, 디할로트리페닐포스포란, 옥살릴 클로라이드 및 포스겐을 포함한다. 인 옥시할라이드 및 인 펜타할라이드가 바람직하다. 이러한 할로겐화를 위한 전형적인 용매는 할로겐화 알칸, 예를 들어 디클로로메탄, 클로로포름, 및 클로로부탄 등, 방향족 용매, 예를 들어 벤젠, 크실렌, 및 클로로벤젠 등, 에테르, 예를 들어 테트라히드로푸란, p-디옥산, 및 디에틸 에테르 등 및 극성 비양자성 용매, 예를 들어 아세토니트릴, 및 N,N-디메틸포름아미드 등을 포함한다. 임의로, 유기 염기, 예를 들어 트리에틸아민, 피리딘, 또는 N,N-디메틸아닐린 등을 첨가할 수 있다. 촉매, 예를 들어 N,N-디메틸포름아미드의 첨가 또한 임의적이다.Halogenation reagents that can be used include phosphorus oxyhalide, phosphorus trihalide, phosphorous pentahalide, thionyl chloride, dihalotrialkylphosphoran, dihalotriphenylphosphoran, oxalyl chloride and phosgene. Preference is given to phosphorus oxyhalides and phosphorus pentahalides. Typical solvents for such halogenation include halogenated alkanes such as dichloromethane, chloroform, and chlorobutane, aromatic solvents such as benzene, xylene, and chlorobenzene, ethers such as tetrahydrofuran, p-di Oxane, diethyl ether, and the like and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. Optionally, organic bases such as triethylamine, pyridine, or N, N-dimethylaniline can be added. The addition of a catalyst, for example N, N-dimethylformamide, is also optional.
별법으로, R4가 할로겐인 화학식 18의 화합물은 R4가 상이한 할로겐 (예를 들어, R4가 Br인 화학식 18의 화합물을 제조하기 위해서는 Cl) 또는 술포네이트기, 예를 들어 메탄술포네이트, 벤젠술포네이트 또는 p-톨루엔술포네이트인 화학식 18 의 상응하는 화합물을 브롬화수소 또는 염화수소로 각각 처리하여 제조할 수 있다. 이 방법에 의해서, 화학식 18의 출발 물질 내의 R4인 할로겐 또는 술포네이트 치환체가 브롬화수소 또는 염화수소 각각으로부터의 Br 또는 Cl로 치환된다. R4가 Cl 또는 Br인 화학식 18의 출발 화합물은 이미 기재된 바와 같이 화학식 20의 상응하는 화합물로부터 제조할 수 있다. R4가 술포네이트기인 화학식 18의 출발 화합물은 표준 방법, 예를 들어 디클로로메탄과 같은 적합한 용매 중에서 술포닐 클로라이드 (예를 들어, 메탄술포닐 클로라이드, 벤젠술포닐 클로라이드, 또는 p-톨루엔술포닐 클로라이드) 및 3급 아민 (예를 들어, 트리에틸아민)과 같은 염기로의 처리에 의해서 화학식 20의 상응하는 화합물로부터 마찬가지로 제조할 수 있다.Alternatively, a compound of formula 18 wherein R 4 is halogen may be a halogen having a different R 4 (eg, Cl to prepare a compound of formula 18 wherein R 4 is Br) or a sulfonate group such as methanesulfonate, Corresponding compounds of formula 18, which are benzenesulfonates or p-toluenesulfonates, can be prepared by treatment with hydrogen bromide or hydrogen chloride, respectively. By this method, the halogen or sulfonate substituent R 4 in the starting material of Formula 18 is replaced with Br or Cl from hydrogen bromide or hydrogen chloride, respectively. Starting compounds of formula 18, wherein R 4 is Cl or Br, can be prepared from the corresponding compounds of formula 20 as already described. Starting compounds of formula (18), wherein R 4 is a sulfonate group, are used in standard methods, for example, in a suitable solvent such as dichloromethane, for example sulfonyl chloride (e.g. methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride And similarly prepared from the corresponding compounds of formula 20 by treatment with bases such as tertiary amines (eg triethylamine).
R4가 OCHF2 또는 OCH2CF3인 화학식 2c의 피라졸카르복실산은 하기 반응식 9에 나타낸 방법에 의해 제조할 수 있다.Pyrazolecarboxylic acids of formula (2c) wherein R 4 is OCHF 2 or OCH 2 CF 3 may be prepared by the method shown in Scheme 9 below.
이 방법에서, 반응식 8에 나타낸 할로겐화 대신에, 화학식 20의 화합물을 화학식 21의 화합물로 산화시킨다. 이러한 산화의 반응 조건은 반응식 7에서 화학식 18의 화합물을 화학식 19의 화합물로 전환시키기 위해서 이미 기재한 바와 같다. 이어서 화학식 21의 화합물을 염기의 존재하에서 CHClF2로부터 동일계에서 제조된 디플루오로카르벤과 접촉시킴으로써 알킬화시켜 화학식 22의 화합물을 형성할 수 있다. 또한 화학식 21의 화합물을 염기의 존재하에서 알킬화 시약인 CF3CH2Lg와 접촉시킴으로써 알킬화시켜 화학식 24의 화합물을 형성할 수 있다. 알킬화 반응은 일반적으로 에테르, 예를 들어 테트라히드로푸란 또는 디옥산, 및 극성 비양자성 용매, 예를 들어 아세토니트릴, N,N-디메틸포름아미드 등을 포함할 수 있는 용매 중에서 수행한다. 염기는 무기 염기, 예를 들어 탄산칼륨, 수산화나트륨 또는 수소화나트륨에서 선택될 수 있다. 바람직하게는 반응은 탄산칼륨과 용매로서 N,N-디메틸포름아미드 또는 아세토니트릴을 사용하여 수행한다. 알킬화 시약 CF3CH2Lg에서, Lg는 핵제거제 (nucleofuge) (즉, 이탈기), 예를 들어 할로겐 (예를 들어, Br, I), OS(O)2CH3 (메탄술포네이트), OS(O)2CF3, 및 OS(O)2Ph-p-CH3 (p-톨루엔술포네이트) 등이다. 화학식 22의 생성물은 통상적인 기술, 예를 들어 추출에 의해서 분리할 수 있다. 이어서 반응식 4에서 화학식 12의 화합물을 화학식 2b의 화합물로 전환시키기 위해서 이미 기재된 방법에 의해서 에스테르를 화학식 2c의 카르복실산으로 전환할 수 있다.In this method, instead of the halogenation shown in Scheme 8, the compound of formula 20 is oxidized to the compound of formula 21. The reaction conditions for this oxidation are as described previously for converting the compound of formula 18 to the compound of formula 19 in Scheme 7. The compound of formula 21 may then be alkylated by contacting difluorocarbene prepared in situ from CHClF 2 in the presence of a base to form a compound of formula 22. The compound of formula 21 may also be alkylated by contacting CF 3 CH 2 Lg, an alkylation reagent, in the presence of a base to form a compound of formula 24. The alkylation reaction is generally carried out in solvents which may include ethers such as tetrahydrofuran or dioxane and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. The base may be selected from inorganic bases such as potassium carbonate, sodium hydroxide or sodium hydride. Preferably the reaction is carried out using potassium carbonate and N, N-dimethylformamide or acetonitrile as solvent. In the alkylation reagent CF 3 CH 2 Lg, Lg is a nucleofuge (ie, leaving group), for example halogen (eg Br, I), OS (O) 2 CH 3 (methanesulfonate), OS (O) 2 CF 3 , OS (O) 2 Ph-p-CH 3 (p-toluenesulfonate), and the like. The product of formula 22 can be separated by conventional techniques, for example by extraction. The ester can then be converted to the carboxylic acid of formula 2c by the method already described in order to convert the compound of formula 12 to the compound of formula 2b in Scheme 4.
화학식 20의 화합물은 반응식 10에서 나타낸 바와 같이 화학식 25의 화합물로부터 제조할 수 있다.Compounds of formula 20 may be prepared from compounds of formula 25 as shown in Scheme 10.
이 방법에서, 화학식 25의 히드라진 화합물을 염기 및 용매의 존재하에서 화학식 26의 화합물 (푸마레이트 에스테르 또는 말레에이트 에스테르 또는 이들의 혼 합물을 사용할 수 있음)과 접촉시킨다. 염기는 전형적으로는 금속 알콕시드염, 예를 들어 나트륨 메톡시드, 칼륨 메톡시드, 나트륨 에톡시드, 칼륨 에톡시드, 칼륨 tert-부톡시드, 및 리튬 tert-부톡시드 등이다. 극성 양자성 및 극성 비양자성 유기 용매, 예를 들어 알콜, 아세토니트릴, 테트라히드로푸란, N,N-디메틸포름아미드, 및 디메틸 술폭시드 등을 사용할 수 있다. 바람직한 용매는 알콜, 예를 들어 메탄올 및 에탄올이다. 알콜이 푸마레이트 또는 말레에이트 에스테르 및 알콕시드 염기에 상응하는 것 (즉, 이들을 구성하는 것과 동일한 것)이 특히 바람직하다. 반응 조건 및 분리 수단에 따라서, 화학식 20의 화합물 내의 -CO2R 관능기가 -CO2H로 가수분해될 수 있고, 예를 들어 반응 혼합물 중의 물의 존재는 이러한 가수분해를 촉진시킬 수 있다. 카르복실산 (-CO2H)이 형성되면, 당업계에 공지된 에스테르화 방법을 사용하여 R이 C1-C4 알킬인 -CO2R로 다시 전환시킬 수 있다. 목적 생성물 화학식 20의 화합물은 당업자에게 공지된 방법, 예를 들어 결정화, 추출 또는 증류에 의해서 분리할 수 있다.In this method, the hydrazine compound of formula 25 is contacted with a compound of formula 26 (which may use fumarate ester or maleate ester or mixtures thereof) in the presence of a base and a solvent. Bases are typically metal alkoxide salts such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide and the like. Polar protic and polar aprotic organic solvents such as alcohols, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like can be used. Preferred solvents are alcohols such as methanol and ethanol. Particular preference is given to those in which the alcohols correspond to fumarate or maleate esters and alkoxide bases (ie the same as what constitutes them). Depending on the reaction conditions and separation means, the -CO 2 R functional group in the compound of formula 20 can be hydrolyzed to -CO 2 H, for example the presence of water in the reaction mixture can promote this hydrolysis. Once the carboxylic acid (-CO 2 H) is formed, it can be converted back to -CO 2 R where R is C 1 -C 4 alkyl using esterification methods known in the art. The desired product The compound of formula 20 can be separated by methods known to those skilled in the art, for example by crystallization, extraction or distillation.
본 발명의 다른 양태는 본 발명의 방법에서 중요한 중간체인 화학식 3의 안트라닐아미드에 관한 것이다. 화학식 3의 안트라닐아미드의 샘플은 또한 안트라닐아미드의 존재를 결정하기 위한 분석 표준물질로서 유용한다.Another aspect of the invention relates to the anthranylamide of formula 3, which is an important intermediate in the process of the invention. Samples of anthraninilamides of Formula 3 are also useful as analytical standards for determining the presence of anthraninilamides.
화학식 3의 안트라닐아미드는 예를 들어 문헌 [L. H. Sternbach et al., J. Org. Chem. 1971, 36, 777-781]에 기재된 절차와 같은 절차를 사용하여 하기 반응식 11에 나타낸 바와 같이 화학식 27의 이사톤산 무수물 (isatoic anhydride)과 암 모니아 또는 알킬아민의 반응으로부터 제조할 수 있다.Anthranylamides of Formula 3 are described, for example, in L. In H. Sternbach et al., J. Org. Chem. 1971, 36, 777-781 can be prepared from the reaction of isatoic anhydride of formula 27 with ammonia or alkylamine as shown in Scheme 11 below.
화학식 27의 이사톤산 무수물은 화학 문헌에 잘 기재되어 있는 다양한 공지된 방법으로 제조할 수 있다. 예를 들어, 이사톤산 무수물은 안트라닐산과 포스겐 또는 포스겐 등가물의 반응을 포함하는 고리화반응을 통해 상응하는 안트라닐산으로부터 수득가능하다. 상기 방법에 중요한 문헌에 대해서는 문헌 [Coppola, Synthesis 1980, 505] 및 [Fabis et al., Tetrahedron, 1998, 10789]을 참고할 수 있다.Istonic anhydride of formula 27 may be prepared by a variety of known methods which are well described in the chemical literature. For example, istonic anhydride is obtainable from the corresponding anthranilic acid via a cyclization reaction involving the reaction of anthranilic acid with a phosgene or phosgene equivalent. For literature important to this method, see Coppola, Synthesis 1980, 505 and Fabis et al., Tetrahedron, 1998, 10789.
화학식 27의 이사톤산 무수물의 합성은 또한 반응식 하기 12에 나타낸 바와 같이 화학식 30의 이사틴으로부터 성취될 수 있다.Synthesis of isatonic anhydride of formula 27 can also be accomplished from isatin of formula 30 as shown in Scheme 12 below.
화학식 30의 이사틴은 예를 들어 문헌 [F. D. Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58] 및 [J. F. M. Da Silva et al., Journal of the Brazilian Chemical Society 2001, 12(3), 273-324]의 절차에 따라서 화학식 29의 아닐린 유도체로부터 수득가능하다. 일반적으로, 이사틴 30을 과산화수소로 산화시켜 상응하는 이사톤산 무수물 28을 양호한 수율로 산출한다 (문헌 [G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223]).Isatin of Formula 30 is described, for example, in F. D. Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58 and [J. F. M. Da Silva et al., Journal of the Brazilian Chemical Society 2001, 12 (3), 273-324, obtainable from aniline derivatives of formula 29. In general, oxidizing isatin 30 with hydrogen peroxide yields the corresponding isotonic acid anhydride 28 in good yield (G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19, 222- 223]).
하기 반응식 13에 나타낸 바와 같이, R2가 Cl, Br 또는 I인 화학식 30의 이사틴은 또한 할로겐화에 의해서 화학식 31의 5-비치환된 이사틴으로부터 수득가능하다. 이어서 시아나이드 치환이 화학식 30a (R2가 CN인 화학식 30)의 이사틴을 제공할 수 있다.As shown in Scheme 13, isatin of Formula 30 wherein R 2 is Cl, Br or I is also obtainable from 5-unsubstituted isatin of Formula 31 by halogenation. The cyanide substitution may then provide isatin of Formula 30a (Formula 30 wherein R 2 is CN).
할로겐화 반응은 문헌에 공지된 많은 시약 및 절차를 사용하여 수행할 수 있다. 적합한 시약은 원소 할로겐 (염소, 브롬, 또는 요오드), "양성 (positive)-할로겐" 시약, 예를 들어 트리클로로이소시아누르산, N-클로로숙신이미드 (NCS), N-브로모숙신이미드 (NBS) 또는 N-요오도숙신이미드 (NIS), 및 할로겐화 시약, 예를 들어 과산화수소 및 히드로겐 할라이드를 포함하는 혼합물을 포함한다. R2가 Cl, Br 또는 I인 화학식 30의 이사틴의 5-위치의 할로겐은 문헌에 공지된 방법을 사용 하여 시아나이드로 치환될 수 있다. 이 방법은 대개 리간드, 예를 들어 치환된 포스핀 또는 치환된 비스포스피노알칸의 존재하에서 일반적으로 금속 화합물을 사용한 시아나이드염의 사용을 포함한다. 적합한 방법은 문헌 [P. E. Maligres et al., Tetrahedron Letters 1999, 40, 8193-8195], 및 [M. Beller et al., Chem. Eur. J. 2003, 9(8), 1828-1836]에 기재된 것과 같이 팔라듐 화합물을 사용하는 방법, 문헌 [S. L. Buchwald in J. Am. Chem. Soc. 2003, 125, 2890-2891]에 기재된 것과 같이 구리 화합물을 사용하는 방법 및 유럽 특허 제384392호, 및 문헌 [K. Sasaki in Bull. Chem. Soc. Japan 2004, 77, 1013-1019], 및 [R. K. Arvela and N. E. Leadbeater in J. Org. Chem. 2003, 68, 9122-9125]에 기재된 것과 같이 니켈 화합물을 사용하는 방법을 포함한다. 당업자는 R1이 Cl인 경우, 시안화 (즉, 시아나이드에 의한 할로겐의 치환)에서 선택성을 얻기 위해서 화학식 30의 R2가 Br 또는 I인 것이 바람직함을 인식할 것이다.Halogenation reactions can be carried out using many reagents and procedures known in the literature. Suitable reagents include elemental halogens (chlorine, bromine, or iodine), "positive-halogen" reagents such as trichloroisocyanuric acid, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS), and mixtures comprising halogenation reagents such as hydrogen peroxide and hydrogen halides. Halogen at the 5-position of isatin of Formula 30 wherein R 2 is Cl, Br or I can be substituted with cyanide using methods known in the literature. This method usually involves the use of cyanide salts with metal compounds, usually in the presence of a ligand such as substituted phosphine or substituted bisphosphinoalkanes. Suitable methods are described in PE Maligres et al., Tetrahedron Letters 1999, 40, 8193-8195, and in M. Beller et al., Chem. Eur. J. 2003, 9 (8), 1828-1836, using a palladium compound as described in SL Buchwald in J. Am. Chem. Soc. 2003, 125, 2890-2891, and methods of using copper compounds and European Patent No. 384392, and K. Sasaki in Bull. Chem. Soc. Japan 2004, 77, 1013-1019, and RK Arvela and NE Leadbeater in J. Org. Chem. 2003, 68, 9122-9125, and methods for using nickel compounds. Those skilled in the art will appreciate that when R 1 is Cl, it is preferred that R 2 in Formula 30 is Br or I in order to obtain selectivity in cyanation (ie substitution of halogen by cyanide).
하기 반응식 14에 나타낸 바와 같이, 화학식 3의 안트라닐아미드는 전형적으로는 니트로기의 촉매화 수소화반응, 그 후 화학식 33의 안트라닐산 에스테르와 암모니아 또는 알킬아민의 반응을 통해 상응하는 화학식 32의 2-니트로벤조산 (또는 에스테르)으로부터 수득가능하다.As shown in Scheme 14 below, the anthranylamides of formula 3 are typically reacted with the corresponding hydrogenated compounds of formula 32 through catalyzed hydrogenation of nitro groups followed by reaction of the anthranilic acid esters of formula 33 with ammonia or alkylamines. Obtainable from nitrobenzoic acid (or ester).
전형적인 환원 절차는 금속 촉매, 예를 들어 탄소 상의 팔라듐 또는 백금 옥시드의 존재하에서 수산기 용매, 예를 들어 에탄올 및 이소프로판올 중에서 수소로의 환원을 포함한다. 환원은 또한 아세트산 중의 아연의 존재하에서 수행할 수 있다. 니트로기를 환원시키기 위한 이들 방법은 화학 문헌에 잘 기록되어 있다. 카르복실산, 에스테르, 및 아미드의 상호전환을 위한 많은 방법도 화학 문헌에 잘 기록되어 있다.Typical reduction procedures involve the reduction to hydrogen in hydroxyl solvents such as ethanol and isopropanol in the presence of a metal catalyst such as palladium or platinum oxide on carbon. Reduction can also be carried out in the presence of zinc in acetic acid. These methods for reducing nitro groups are well documented in the chemical literature. Many methods for the interconversion of carboxylic acids, esters, and amides are also well documented in the chemical literature.
하기 반응식 15에 나타낸 바와 같이, 화학식 3의 안트라닐아미드는 또한 할로겐화에 의해서 화학식 34의 5-비치환된 안트라닐아미드로부터 수득가능하고, 이것은 R2가 Br, Cl 또는 I인 화학식 3의 안트라닐아미드를 제공하고, 그 후 임의로 시아나이드 치환에 의해 화학식 3a (R2가 CN인 화학식 3)의 안트라닐아미드를 제공한다.As shown in Scheme 15 below, the anthranylamides of formula 3 are also obtainable from halogenated 5-unsubstituted anthranylamides of formula 34, which is an anthranyl of formula 3 wherein R 2 is Br, Cl or I Amide is then provided, optionally by cyanide substitution, to provide anthranilamide of Formula 3a (Formula 3 wherein R 2 is CN).
적합한 방법 및 절차는 문헌에 공지되어 있고 반응식 13에 나타낸 할로겐화 및 시아나이드 치환에 대해 기재한 것과 유사하다. 당업자는 할로겐화 및 시안화는 또한 화학식 3의 안트라닐아미드의 제조에서 다른 단계에서 수행할 수 있음을 인식할 것이다.Suitable methods and procedures are similar to those described for the halogenation and cyanide substitutions known in the literature and shown in Scheme 13. Those skilled in the art will appreciate that halogenation and cyanation may also be carried out in other steps in the preparation of the anthranylamides of formula (3).
화학식 2의 화합물 및 화학식 3의 화합물을 제조하기 위해서 상기에 기재한 일부 시약 및 반응 조건은 중간체 내에 존재하는 특정 관능기와 상용성이 아닐 수도 있다는 것을 인지할 것이다. 이런 경우에, 합성에 보호/탈보호 순서 또는 관능기 상호전환을 추가하여 목적 생성물을 수득하는 것을 보조할 것이다. 보호기의 사용 및 선택은 화학 합성분야의 숙련자들에게 자명할 것이다 (예를 들어, 문헌 [Greene, T. W., Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed., Wiley, New York, 1991] 참고). 당업자는 일부 경우에서, 화학식 2의 화합물 및 화학식 3의 화합물의 합성을 완결하기 위해서 임의의 개별 반응식에서 도시되었을 때 주어진 시약의 도입 후에 상세하게 기재하지 않은 추가의 일상적인 합성 단계를 수행하는 것이 필요할 수도 있음을 인식할 것이다. 당업자는 상기 반응식에 설명된 단계의 배합을 또한 화학식 2의 화합물 및 화학식 3의 화합물을 제조하기 위해 제공된 특정 순서에 함축된 것 이외의 다른 순서로 수행하는 것이 필요할 수도 있음을 인식할 것이다. 당업자는 또한 화학식 2의 화합물 및 화학식 3의 화합물 및 본원에 기재된 중간체는 다양한 친전자성 반응, 친핵성 반응, 라디칼 반응, 유기금속 반응, 산화 반응 및 환원 반응에 적용되어 치환체가 추가되거나 또는 존재하는 치환체가 개질될 수 있음을 인식할 것이다.It will be appreciated that some of the reagents and reaction conditions described above for preparing compounds of Formula 2 and compounds of Formula 3 may not be compatible with the specific functional groups present in the intermediate. In this case, adding a protective / deprotective sequence or functional interconversion to the synthesis will assist in obtaining the desired product. The use and selection of protecting groups will be apparent to those skilled in chemical synthesis (see, e.g., Greene, T. W., Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed., Wiley, New York, 1991). Those skilled in the art will, in some cases, need to perform additional routine synthetic steps that are not described in detail after introduction of a given reagent when shown in any individual scheme to complete the synthesis of the compound of Formula 2 and the compound of Formula 3 It will be appreciated. Those skilled in the art will appreciate that it may be necessary to carry out the combination of steps described in the above schemes in an order other than those implied in the particular order provided for the preparation of the compounds of formula (2) and compounds of formula (3). Those skilled in the art will also appreciate that compounds of formula (2) and compounds of formula (3) and intermediates described herein are subjected to various electrophilic reactions, nucleophilic reactions, radical reactions, organometallic reactions, oxidation reactions, and reduction reactions to which substituents are added or present. It will be appreciated that substituents may be modified.
추가의 노력 없이, 당업자는 상기 설명을 사용하여 완전하게 본 발명을 활용할 수 있다고 생각된다. 따라서 하기 실시예는 단지 설명으로서만 해석되어야 하고 어떤 경우에든 본원을 제한하고자 함이 아니다. 하기 실시예의 단계는 전반적인 합성 변환에서 각 단계에 대한 절차를 설명하고, 각 단계의 출발 물질은 다른 실시예 또는 단계에서 기재된 특정 예비 수행의 절차에 의해서 반드시 제조된 것이 아닐 수 있다. 크로마토그래피 용매 혼합물을 제외하고 또는 달리 지시되지 않으면 백분율은 중량을 기준으로 한다. 달리 지시되지 않으면 크로마토그래피 용매 혼합물에 대한 부 및 백분율은 부피를 기준으로 한다. 1H NMR 스펙트럼은 테트라메틸실란으로부터의 ppm 다운필드로 기록하였고, s는 단일항, d는 이중항, t는 삼중항, q는 사중항, m은 다중항, dd는 이중항의 이중항, dt는 삼중항의 이중항, br s는 넓은 단일항이다. 에이스 (Ace) C18 또는 C4 울트라 이너트® (Ultra Inert®) 크로마토그래피 컬럼 (미국 19317 펜실배니아주 채드 포드에 소재한 맥모드 아날리티컬 인크 (MacMod Analytical Inc.)에서 제조한 역상 컬럼) (입자 크기 3 ㎛, 4.6 mm x 15 cm, 용리액 5에서 80%로의 아세토니트릴/ pH 3 포스페이트 완충액)을 사용하여 생성물의 정량 HPLC를 수행하였다.Without further effort, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest. The following examples are, therefore, to be construed as illustrative only and are not intended to limit the invention in any case. The steps of the following examples describe the procedures for each step in the overall synthetic transformation, and the starting material of each step may not necessarily be prepared by the specific preliminary procedure described in other examples or steps. Percentages are by weight except for chromatographic solvent mixtures or unless otherwise indicated. Parts and percentages for chromatographic solvent mixtures are based on volume unless otherwise indicated. 1 H NMR spectra were reported in ppm downfield from tetramethylsilane, where s is singlet, d is doublet, t is triplet, q is quadruple, m is multiplet, dd is doublet, dt Is a triplet of triplets, br s is a broad singlet. Ace C18 or C4 Ultra Inert® Chromatography Columns (Reverse Phase Columns manufactured by MacMod Analytical Inc., Chad Ford, 19317, PA) (particle size) Quantitative HPLC of the product was performed using 3 μm, 4.6 mm × 15 cm, eluent 5 to 80% acetonitrile / pH 3 phosphate buffer).
실시예 1Example 1
2-아미노-5-2-Amino-5- 클로로Chloro -N,3--N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
아세토니트릴 (700 mL) 중의 6-클로로-8-메틸-2H-3,1-벤족사진-2,4(1H)-디온 (211.6 g, 1000 mmol)의 현탁액에 아세트산 (7.3 g, 122 mmol)을 첨가하였다. 이어서 40% 수성 메틸아민 (104 mL)을 25 내지 30℃에서 30분에 걸쳐 적가하였다. 교반을 2시간 동안 계속한 후, 물 (700 mL)을 천천히 첨가하였다. 생성된 현탁액을 5℃로 냉각하고, 30분 동안 이 온도에서 교반하였다. 이어서 현탁액을 여과하고, 고형물을 물 (3 x 200 mL)로 세척하고, 질소 하에서 건조시켜 회백색 바늘형으로서 표제 화합물을 산출하였다 (172.8 g (수율 87.0%)).Acetic acid (7.3 g, 122 mmol) in a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione (211.6 g, 1000 mmol) in acetonitrile (700 mL) Was added. 40% aqueous methylamine (104 mL) was then added dropwise at 25-30 ° C. over 30 minutes. Stirring was continued for 2 hours, then water (700 mL) was added slowly. The resulting suspension was cooled to 5 ° C. and stirred at this temperature for 30 minutes. The suspension was then filtered, the solid was washed with water (3 x 200 mL) and dried under nitrogen to yield the title compound as an off-white needle (172.8 g (87.0% yield)).
실시예 2 Example 2
메틸 2-아미노-5-클로로-3-메틸벤조에이트의 제조Preparation of Methyl 2-amino-5-chloro-3-methylbenzoate
단계 A: 2-아미노-5-Step A: 2-Amino-5- 클로로Chloro -3--3- 메틸벤조산의Methylbenzoic acid 제조 Produce
N,N-디메틸포름아미드 (50 mL) 중의 2-아미노-3-메틸벤조산 (알드리치 (Aldrich), 15.0 g, 99.2 mmol)의 용액에 N-클로로숙신이미드 (13.3 g, 99.2 mmol)를 첨가하고, 반응 혼합물을 30분 동안 100℃로 가열하였다. 가열기를 제거하고, 반응 혼합물을 실온으로 냉각하고, 밤새 방치하였다. 이어서 반응 혼합물을 빙수 (250 mL) 내에 천천히 부어서 백색 고형물을 침전시켰다. 고형물을 여과하고, 물로 4회 세척한 후, 에틸 아세테이트 (900 mL) 중에 취했다. 에틸 아세테이트 용액을 건조시키고 (MgSO4), 감압하에서 증발시키고, 잔류 고형물을 에테르로 세척하여 백색 고체로서 목적 중간체를 산출하였다 (13.9 g (수율 75.4%)).N-chlorosuccinimide (13.3 g, 99.2 mmol) is added to a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N, N-dimethylformamide (50 mL). And the reaction mixture was heated to 100 ° C. for 30 minutes. The heater was removed and the reaction mixture was cooled to room temperature and left overnight. The reaction mixture was then poured slowly into ice water (250 mL) to precipitate a white solid. The solid was filtered off, washed four times with water and taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried (MgSO 4 ), evaporated under reduced pressure, and the residual solid washed with ether to yield the desired intermediate as a white solid (13.9 g (75.4% yield)).
단계 B: Step B: 메틸methyl 2-아미노-5- 2-Amino-5- 클로로Chloro -3--3- 메틸벤조에이트의Methylbenzoate 제조 Produce
0 내지 5℃에서 아세토니트릴 (500 mL) 중의 2-아미노-5-클로로-3-메틸벤조산 (즉, 단계 A의 생성물) (92.8 g, 500 mmol)의 현탁액에 1,4-디아자-비시클로[5.4.0]운데크-7-엔 (DBU, 90 mL, 92 g, 600 mmol)을 첨가한 후, 디메틸 술페이트 (57 mL, 76 g, 600 mmol)을 0 내지 5℃에서 적가하였다. 이 온도에서 3시간 동안 교반한 후, 추가의 DBU (15 mL) 및 디메틸 술페이트 (10 mL)를 첨가하였다. 이 온도에서 3시간 더 교반한 후, 추가의 DBU (15 mL) 및 디메틸 술페이트 (10 mL)를 첨가하였다. 이 온도에서 2시간 더 교반한 후, 진한 염산 (60 mL, 720 mmol)을 0 내지 10℃에서 적가하였다. 생성된 현탁액을 30분 동안 0 내지 5℃에서 교반한 후, 여과하고, 고형물을 얼음 냉각된 2:1 물-아세토니트릴 (3 x 100 mL)로 세척하고, 질소 하에서 건조시켰다. 조 생성물을 메탄올 (250 mL) 중에 현탁시키고, 물 (1000 mL)을 첨가하고, 혼합물을 실온에서 1시간 동안 교반하였다. 이어서 고형물을 여과하고, 4:1 물-메탄올 (100 mL), 이어서 물 (3 x 100 mL)로 세척하고, 질소 하에서 건조시켜 융점이 낮은 백색 고형물로서 표제 화합물을 산출하였다 (87.6 g (수율 87.8%)). 고형 생성물의 HPLC는 표제 에스테르가 99.7 면적%로 존재함을 나타내었다. 1,4-diaza-ratio in a suspension of 2-amino-5-chloro-3-methylbenzoic acid (ie, the product of Step A) (92.8 g, 500 mmol) in acetonitrile (500 mL) at 0-5 ° C. Cyclo [5.4.0] undec-7-ene (DBU, 90 mL, 92 g, 600 mmol) was added and then dimethyl sulfate (57 mL, 76 g, 600 mmol) was added dropwise at 0-5 ° C. . After stirring for 3 hours at this temperature, additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After 3 hours more stirring at this temperature, additional DBU (15 mL) and dimethyl sulphate (10 mL) were added. After 2 hours more stirring at this temperature, concentrated hydrochloric acid (60 mL, 720 mmol) was added dropwise at 0-10 ° C. The resulting suspension was stirred for 30 minutes at 0-5 ° C., then filtered and the solid was washed with ice cooled 2: 1 water-acetonitrile (3 × 100 mL) and dried under nitrogen. The crude product was suspended in methanol (250 mL), water (1000 mL) was added and the mixture was stirred at rt for 1 h. The solid was then filtered off, washed with 4: 1 water-methanol (100 mL), followed by water (3 × 100 mL) and dried under nitrogen to yield the title compound as a low melting white solid (87.6 g (yield 87.8). %)). HPLC of the solid product showed that the title ester was present at 99.7 area%.
실시예 3Example 3
2-아미노-5-2-Amino-5- 클로로Chloro -N,3--N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
아세토니트릴 (12.4 g) 중의 메틸 2-아미노-5-클로로-3-메틸벤조에이트 (즉, 실시예 2의 생성물) (4.03 g, 20.2 mmol)의 현탁액에 에틸렌 글리콜 (12.4 g) 중의 메틸아민 (3.1 g, 0.10 mol)의 용액을 첨가하였다. 혼합물을 23시간 동안 60℃에서 가열한 후, 실온으로 냉각하였다. 물 (25 mL)을 적가하고, 생성된 슬러리를 5℃로 냉각하고, 이 온도에서 10분 동안 교반하였다. 혼합물을 여과하고, 고형물을 물 (3 x 10 mL)로 세척하고, 질소 하에서 건조시켜 백색 바늘형으로서 표제 화합물을 산출하였다 (3.43 g (수율 85.5%)).Methylamine in ethylene glycol (12.4 g) in a suspension of methyl 2-amino-5-chloro-3-methylbenzoate (ie the product of Example 2) (4.03 g, 20.2 mmol) in acetonitrile (12.4 g) ( 3.1 g, 0.10 mol) of solution was added. The mixture was heated at 60 ° C. for 23 hours and then cooled to room temperature. Water (25 mL) was added dropwise and the resulting slurry was cooled to 5 ° C. and stirred at this temperature for 10 minutes. The mixture was filtered and the solid washed with water (3 × 10 mL) and dried under nitrogen to yield the title compound as a white needle (3.43 g (85.5% yield)).
실시예 4Example 4
2-아미노-5-클로로-N,3-디메틸벤자미드의 제조Preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide
단계 A: Step A: 메틸methyl 2-아미노-3- 2-amino-3- 메틸벤조에이트의Methylbenzoate 제조 Produce
메틸 3-메틸-2-니트로벤조에이트 (98.5 g, 505 mmol), 5% Pd/C (데구사 (Degussa) CE 105 XRC/W, 1.0 g), 및 아세토니트릴 (300 mL)을 600-mL 압력 용기 중에서 배합하였다. 혼합물을 70℃로 가열하고, 65 psi (450 kPa)에서 8시간 동안 수소화시켰다. 추가의 5% Pd/C (1.0 g)를 첨가하고, 100 psi (690 kPa)에서 8.5 시간 동안 수소화를 계속하였다. 이어서 반응 혼합물을 냉각하고, 질소로 퍼징하고, 셀라이트® 규조류 여과 보조기를 통해 여과하고, 아세토니트릴 (3 x 25 mL)로 헹구었다. 합한 여과액을 약 160 g의 중량으로 부분적으로 증발시킨 후, 200 g의 총 중량으로 아세토니트릴로 희석하였다. 이 용액의 정량 HPLC는 표제 화합물이 40.3 중량%로 존재함을 나타내었다 (80.6 g, 수율 97.5%).600-mL of methyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5% Pd / C (Degussa CE 105 XRC / W, 1.0 g), and acetonitrile (300 mL) Compounded in pressure vessel. The mixture was heated to 70 ° C. and hydrogenated at 65 psi (450 kPa) for 8 hours. Additional 5% Pd / C (1.0 g) was added and hydrogenation continued at 100 psi (690 kPa) for 8.5 hours. The reaction mixture was then cooled, purged with nitrogen, filtered through a Celite® diatom filter aid and rinsed with acetonitrile (3 x 25 mL). The combined filtrates were partially evaporated to a weight of about 160 g and then diluted with acetonitrile to a total weight of 200 g. Quantitative HPLC of this solution showed the title compound was present at 40.3% by weight (80.6 g, yield 97.5%).
단계 B: Step B: 메틸methyl 2-아미노-5- 2-Amino-5- 클로로Chloro -3--3- 메틸벤조에이트의Methylbenzoate 제조 Produce
단계 A에서 제조한 용액 (195 g, 475 mmol)을 아세토니트릴 (50 mL)로 희석하고, 50℃로 가열하였다. 이어서 아세토니트릴 (100 mL) 중의 술푸릴 클로라이드 (70.6 g, 523 mmol)의 용액을 50 내지 55℃에서 3.25 시간에 걸쳐 첨가하였다. 첨가가 완료된 직후, 혼합물을 5℃로 냉각하고, 물 (150 g)을 첨가하고, 50% 수성 수산화나트륨 (103 g)을 천천히 첨가하여 용액의 pH를 6.0으로 조정하였다. 이 온도에서 10분 동안 교반한 후, 유기층을 분리하고, 수층을 아세토니트릴 (50 mL)로 추출하였다. 유기층을 합하고, 건조하고 (MgSO4), 193.7 g의 중량으로 부분적으로 증발시켰다. 이 용액의 정량 HPLC는 표제 화합물이 41.5 중량%로 존재함을 나타내었다 (80.4 g, 수율 84.8%).The solution prepared in step A (195 g, 475 mmol) was diluted with acetonitrile (50 mL) and heated to 50 ° C. Then a solution of sulfuryl chloride (70.6 g, 523 mmol) in acetonitrile (100 mL) was added at 50-55 ° C. over 3.25 h. Immediately after the addition was complete, the mixture was cooled to 5 ° C., water (150 g) was added, and 50% aqueous sodium hydroxide (103 g) was added slowly to adjust the pH of the solution to 6.0. After stirring for 10 min at this temperature, the organic layer was separated and the aqueous layer was extracted with acetonitrile (50 mL). The organic layers were combined, dried (MgSO 4 ) and partially evaporated to a weight of 193.7 g. Quantitative HPLC of this solution showed the title compound was present at 41.5% by weight (80.4 g, yield 84.8%).
단계 C: 2-아미노-5-Step C: 2-Amino-5- 클로로Chloro -N,3--N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
단계 B에서 제조한 용액 (96.2 g, 200 mmol)을 아세토니트릴 (60.0 g) 및 에틸렌 글리콜 (180 g)로 희석하고, 클라이젠 (Claisen) 증류 헤드 하에서 대기압에서 증류시킴으로써 공비적으로 건조시켜서 약 72 mL의 휘발물질을 제거하였다. 이 어서 증류 헤드를 건조-얼음-냉각 (dry-ice-cooled) 응축기로 교체하고, 잔류 용액을 0 내지 5℃로 냉각하고, 반응 혼합물의 표면 아래로 메틸아민 기체 (31.1 g, 1000 mmol)를 첨가하였다. 혼합물을 17.5시간 동안 70℃에서 가열한 후, 물 (400 mL)을 천천히 첨가하여 생성물을 침전시켰다. 혼합물을 5℃로 천천히 냉각하고, 이 온도에서 15분 동안 교반하고, 여과하고, 고형물을 물로 세척하고 질소 하에서 건조시켜 목적 화합물을 산출하였다 (36.36 g, 91.5% 수율). HPLC는 순도가 99.3 면적%임을 나타내었다.The solution prepared in step B (96.2 g, 200 mmol) was diluted with acetonitrile (60.0 g) and ethylene glycol (180 g) and azeotropically dried by distillation at atmospheric pressure under a Claisen distillation head to about 72 mL of volatiles was removed. The distillation head was then replaced with a dry-ice-cooled condenser, the residual solution was cooled to 0-5 ° C., and methylamine gas (31.1 g, 1000 mmol) was lowered below the surface of the reaction mixture. Added. The mixture was heated at 70 ° C. for 17.5 h, then water (400 mL) was added slowly to precipitate the product. The mixture was cooled slowly to 5 ° C., stirred at this temperature for 15 minutes, filtered and the solid washed with water and dried under nitrogen to yield the desired compound (36.36 g, 91.5% yield). HPLC showed that the purity was 99.3 area%.
실시예 5Example 5
2-아미노-5-클로로-N,3-디메틸벤자미드의 제조Preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide
단계 A: 2-아미노-N,3-Step A: 2-amino-N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
에틸 아세테이트 (200 mL) 중의 8-메틸-2H-3,1-벤족사진-2,4(1H)-디온 (PCT 특허 공개 제WO 00/27831호) (18 g, 0.1 mol) 및 아세트산 (1.2 g, 0.02 mol)의 혼합물을 35℃로 가온하고, 수성 메틸아민 (40%, 9.0 g, 0.12 mol)을 35 내지 37℃에서 50분에 걸쳐서 적가하였다. 이어서 추가의 수성 메틸아민 (40%, 0.9 g, 12 mmol)을 첨가하고, 혼합물을 추가 2.5시간 동안 36℃에서 교반하였다. 이어서 물 (20 mL)을 첨가하고, 층을 분리하고, 유기층을 물로 세척하고, 건조하고 (MgSO4), 증발시켜 표제 화합물을 산출하였다 (15.45 g (92%)).8-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione (PCT Patent Publication WO 00/27831) (18 g, 0.1 mol) and acetic acid (1.2 in ethyl acetate (200 mL) g, 0.02 mol) was warmed to 35 ° C. and aqueous methylamine (40%, 9.0 g, 0.12 mol) was added dropwise at 35-37 ° C. over 50 minutes. Then additional aqueous methylamine (40%, 0.9 g, 12 mmol) was added and the mixture was stirred at 36 ° C. for an additional 2.5 hours. Water (20 mL) was then added, the layers separated and the organic layer washed with water, dried (MgSO 4 ) and evaporated to yield the title compound (15.45 g (92%)).
단계 B: 2-아미노-5-Step B: 2-Amino-5- 클로로Chloro -N,3--N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
2-아미노-N,3-디메틸벤자미드 (즉, 단계 A의 생성물) (16.6 g, 100 mmol) 및 N,N-디메틸포름아미드 (15.0 g)의 혼합물을 10℃로 냉각하고, 진한 염산 (70 g, 700 mmol)을 천천히 첨가하였다. 이어서 혼합물을 30℃로 가열하고, 30% 수성 과산화수소 (18.5 g, 160 mmol)를 30 내지 35℃에서 15분에 걸쳐서 적가하였다. 약 35℃에서 3시간 동안 교반한 후, 혼합물을 약 10℃로 냉각한 후, 물 (200 mL)을 첨가하였다. 나트륨 술파이트 (7.56 g, 60 mmol)를 첨가한 후, 50% 수성 수산화나트륨 (38.1 g)을 천천히 첨가하여 pH를 2.2로 조정하였다. 10℃에서 15분 동안 교반한 후, 혼합물을 여과하고, 고형물을 물 (2 x 50 mL)로 세척하고, 진공 오븐에서 건조시켜 분홍색 고형물로서 표제 화합물을 산출하였다 (14.61 g (수율 72.7%)). 고형 생성물의 정량 HPLC는 표제 화합물이 99.1 중량% 존재함을 나타내었다. A mixture of 2-amino-N, 3-dimethylbenzamide (ie, the product of Step A) (16.6 g, 100 mmol) and N, N-dimethylformamide (15.0 g) was cooled to 10 ° C. and concentrated hydrochloric acid ( 70 g, 700 mmol) was added slowly. The mixture was then heated to 30 ° C. and 30% aqueous hydrogen peroxide (18.5 g, 160 mmol) was added dropwise at 30-35 ° C. over 15 minutes. After stirring at about 35 ° C. for 3 hours, the mixture was cooled to about 10 ° C. and then water (200 mL) was added. After addition of sodium sulfite (7.56 g, 60 mmol), the pH was adjusted to 2.2 by slowly adding 50% aqueous sodium hydroxide (38.1 g). After stirring at 10 ° C. for 15 minutes, the mixture is filtered, the solid is washed with water (2 × 50 mL) and dried in a vacuum oven to yield the title compound as a pink solid (14.61 g (72.7% yield)). . Quantitative HPLC of the solid product showed 99.1 wt% of the title compound.
실시예 6Example 6
2-아미노-5-시아노-N,3-디메틸벤자미드의 제조 Preparation of 2-amino-5-cyano-N, 3-dimethylbenzamide
단계 A: 2-아미노-5-Step A: 2-Amino-5- 브로모Bromo -N,3--N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
2-아미노-N,3-디메틸벤자미드 (즉, 실시예 5의 단계 A의 생성물) (14 g, 85 mmol), 아세트산 (50 mL), 및 물 (50 mL)의 혼합물을 12℃로 냉각하고, 진한 브롬수소산 (28.5 g, 0.34 mol)을 이 온도에서 10분에 걸쳐서 첨가하였다. 이어서 30% 수성 과산화수소 (9 g, 0.08 mol)를 10 내지 11℃에서 5분에 걸쳐서 첨가하고, 2.5시간 교반하면서 혼합물을 실온으로 천천히 승온시켰다. 이어서 추가의 진한 브롬수소산 (2.9 g)을 첨가하고, 혼합물을 밤새 실온에서 교반하였다. 이어서 혼합물에 물 (5O mL), 나트륨 비술파이트 (1.5 g)를 첨가한 후, 50% 수성 수산화나 트륨 (약 15 mL)을 첨가하여 pH를 5 내지 6으로 조정하였다. 혼합물을 여과하고, 고형물을 물로 세척하고, 진공에서 건조시켜 표제 화합물을 산출하였다 (19.5 g (94%)).A mixture of 2-amino-N, 3-dimethylbenzamide (ie, the product of Step A of Example 5) (14 g, 85 mmol), acetic acid (50 mL), and water (50 mL) was cooled to 12 ° C. Concentrated hydrobromic acid (28.5 g, 0.34 mol) was added at this temperature over 10 minutes. 30% aqueous hydrogen peroxide (9 g, 0.08 mol) was then added at 10-11 ° C. over 5 minutes and the mixture was slowly warmed to room temperature with stirring for 2.5 hours. Then additional concentrated hydrobromic acid (2.9 g) was added and the mixture was stirred at rt overnight. To the mixture was then added water (50 mL), sodium bisulfite (1.5 g), and then the pH was adjusted to 5-6 by addition of 50% aqueous sodium hydroxide (about 15 mL). The mixture was filtered, the solid was washed with water and dried in vacuo to yield the title compound (19.5 g (94%)).
단계 B: 2-아미노-5-Step B: 2-Amino-5- 시아노Cyano -N,3--N, 3- 디메틸벤자미드의Of dimethylbenzamide 제조 Produce
무수 질소로 퍼징된 플라스크에 팔라듐(II) 아세테이트 (370 mg, 1.64 mmol), 1,4-비스(디페닐포스피노)부탄 (850 mg, 2 mmol), 활성 아연 분말 (500 mg, 7.64 mmol), 시안화아연(II) (51 g, 434 mmol), 및 2-아미노-5-브로모-N,3-디메틸벤자미드 (즉, 단계 A의 생성물) (200 g, 820 mmol)를 충전시켰다. 이어서 새로 탈기된 N,N-디메틸포름아미드 (500 mL)를 첨가하고, 혼합물을 25.5시간 동안 130℃에서 가열하였다. 이어서 온도를 95℃로 내리고, 아세트산 (200 mL)을 첨가하였다. 실온으로 냉각하는 동안 혼합물에 질소를 살포하여 수성 수산화나트륨 및 나트륨 하이포클로라이트 용액이 충전된 집진기 (scrubber)를 통해 시안화수소를 제거하였다. 이어서 물 (1500 mL)을 1.5시간에 걸쳐 첨가하고, 질소 살포를 밤새 계속하였다. 이어서 혼합물을 여과하고, 고형물을 물로 세척하고, 진공 오븐에서 건조시켜 솜털형 연황색 고체로서 표제 화합물을 산출하였다 (141.5 g (수율 90.9%)). Palladium (II) acetate (370 mg, 1.64 mmol), 1,4-bis (diphenylphosphino) butane (850 mg, 2 mmol), activated zinc powder (500 mg, 7.64 mmol) in a flask purged with anhydrous nitrogen , Zinc cyanide (II) (51 g, 434 mmol), and 2-amino-5-bromo-N, 3-dimethylbenzamide (ie, the product of Step A) (200 g, 820 mmol) were charged. Freshly degassed N, N-dimethylformamide (500 mL) was then added and the mixture was heated at 130 ° C. for 25.5 h. The temperature was then lowered to 95 ° C. and acetic acid (200 mL) was added. Hydrogen cyanide was removed through a scrubber filled with aqueous sodium hydroxide and sodium hypochlorite solution by sparging nitrogen with the mixture while cooling to room temperature. Water (1500 mL) was then added over 1.5 hours and nitrogen sparging continued overnight. The mixture was then filtered, the solid was washed with water and dried in a vacuum oven to yield the title compound as a downy pale yellow solid (141.5 g (yield 90.9%)).
실시예 7 Example 7
3-3- 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )카르보닐]) Carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (35 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 93.6%, 16.16 g, 50.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (즉, 실시예 1, 3, 4 및 5의 생성물) (10.43 g, 52.5 mmol)의 혼합물에 3-피콜린 (12.65 mL, 12.11 g, 130 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 아세토니트릴 (10 mL) 중의 메탄술포닐 클로라이드의 용액 (4.64 mL, 6.89 g, 60 mmol)을 -5 내지 0℃에서 적가하였다. 혼합물을 이 온도에서 15분 동안, 이어서 실온에서 3시간 동안 교반하였다. 이어서 물 (15 mL)을 적가하고, 혼합물을 1시간 동안 0℃로 냉각하였다. 혼합물을 여과하고, 고형물을 3:1 아세토니트릴-물 (2 x 10 mL)로, 이어서 아세토니트릴 (2 x 10 mL)로 세척하고, 질소 하에서 건조시켜 연갈색 분말로서 표제 화합물을 산출하였다 (23.98 g (부정확한 수율 92.9%)). m.p. 239 내지 240℃.3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (35 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) (Purity 93.6%, 16.16 g, 50.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie the product of Examples 1, 3, 4 and 5) (10.43 g, 52.5 mmol) 3-picoline (12.65 mL, 12.11 g, 130 mmol) was added to the mixture. After the mixture was cooled to -5 ° C, a solution of methanesulfonyl chloride (4.64 mL, 6.89 g, 60 mmol) in acetonitrile (10 mL) was added dropwise at -5 to 0 ° C. The mixture was stirred at this temperature for 15 minutes and then at room temperature for 3 hours. Water (15 mL) was then added dropwise and the mixture was cooled to 0 ° C. for 1 hour. The mixture was filtered and the solid was washed with 3: 1 acetonitrile-water (2 x 10 mL) and then with acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as a light brown powder (23.98 g (Incorrect yield 92.9%)). m.p. 239 to 240 ° C.
실시예 8Example 8
염기로서 피리딘을 사용하는 3-3- using pyridine as base 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )카르보닐]) Carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (즉, 실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 피리딘 (4.20 mL, 4.11 g, 52 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 이 온도에서 1시간 동안, 이어서 실온에서 3시간 동안 교반하였다. 이어서 물 (6 mL)을 적가하고, 혼합물을 실온에서 1시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 3:1 아세토니트릴-물 (2 x 4 mL)로, 이어서 아세토니트릴 (2 x 4 mL)로 세척하고, 질소 하에서 건조시켜 회백색 분말로서 표제 화합물을 산출하였다 (9.35 g (부정확한 수율 96.8%)).3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) (6.05 g, 20.0 mmol) and pyridine in a mixture of 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, the products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) 4.20 mL, 4.11 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at this temperature for 1 hour and then at room temperature for 3 hours. Water (6 mL) was then added dropwise and the mixture was stirred at rt for 1 h. The mixture was filtered and the solid was washed with 3: 1 acetonitrile-water (2 x 4 mL) and then with acetonitrile (2 x 4 mL) and dried under nitrogen to yield the title compound as an off-white powder (9.35 g (Incorrect yield 96.8%)).
실시예 9Example 9
염기로서 "혼합된 피콜린"을 사용하는 3-3- using "mixed picoline" as base 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(메틸아미노)카르보닐]-6-[(methylamino) carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해서 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (즉, 실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 3-피콜린 (2.53 mL, 2.42 g, 26 mmol), 이어서 4-피콜린 (2.53 mL, 2.42 g, 26 mmol)을 첨가하였다. 4-피콜린을 첨가한 후, 혼합물이 매우 진해졌다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 0 내지 5℃에서 2시간 동안 교반하였다. 이어서 물 (6 mL)을 적가하고, 혼합물을 0℃에서 1 시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 3:1 아세토니트릴-물 (2 x 4 mL)로, 이어서 아세토니트릴 (2 x 4 mL)로 세척하고, 질소 하에서 건조시켜 황색 분말로서 표제 화합물을 산출하였다 (9.15 g (부정확한 수율 94.7%)).3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3- in a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (2.53 mL, 2.42 g, 26 mmol) was added followed by 4-picoline (2.53 mL, 2.42 g, 26 mmol). After adding 4-picoline, the mixture became very thick. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 2 hours. Water (6 mL) was then added dropwise and the mixture was stirred at 0 ° C. for 1 hour. The mixture was filtered and the solid was washed with 3: 1 acetonitrile-water (2 x 4 mL) and then with acetonitrile (2 x 4 mL) and dried under nitrogen to yield the title compound as a yellow powder (9.15 g (Incorrect yield 94.7%)).
실시예 10 Example 10
아세톤 중의 3-3- in acetone 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(메틸아미노)카르보닐]-6-[(methylamino) carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세톤 (18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (즉,실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 3-피콜린 (5.06 mL, 4.84 g, 52 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 물 (9 mL)을 적가하고, 혼합물을 0℃에서 1시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 얼음 냉각된 2:1 아세톤-물 (2 x 4 mL)로 세척하고, 질소 하에서 건조시켜 거의 백색인 분말로서 표제 화합물을 산출하였다 (9.32 g (부정확한 수율 96.4%)).3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetone (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) ( 6.05 g, 20.0 mmol) and 3-pi in a mixture of 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, the products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Choline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at 0 ° C for 1 h. The mixture was filtered and the solid was washed with ice cold 2: 1 acetone-water (2 × 4 mL) and dried under nitrogen to yield the title compound as an almost white powder (9.32 g (incorrect yield 96.4%)). ).
실시예 11Example 11
테트라히드로푸란 중의 3-3- in tetrahydrofuran 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )카르보닐]) Carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
테트라히드로푸란 (THF, 18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 3-피콜린 (5.06 mL, 4.84 g, 52 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 물 (9 mL)을 적가하고, 혼합물을 0℃에서 1시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 얼음 냉각된 2:1 THF-물 (2 x 4 mL)로 세척하고, 질소 하에서 건조시켜 거의 백색인 분말로서 표제 화합물을 산출하였다 (6.93 g (부정확한 수율 71.7%)).3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in tetrahydrofuran (THF, 18 mL) (PCT Patent Publication WO 03/015519 for the preparation) 3) to a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at 0 ° C for 1 h. The mixture was filtered and the solid washed with ice cold 2: 1 THF-water (2 × 4 mL) and dried under nitrogen to yield the title compound as an almost white powder (6.93 g (incorrect yield 71.7%)). ).
실시예 12 Example 12
디클로로메탄 중의 3-3- in dichloromethane 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )카르보닐]) Carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
디클로로메탄 (18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (즉,실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 3-피콜린 (5.06 mL, 4.84 g, 52 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 물 (9 mL)을 적가하였다. 추가의 디클로로메탄 (18 mL)을 첨가 하여 진한 현탁액을 교반하고, 혼합물을 0℃에서 1시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 얼음 냉각된 2:1 디클로로메탄-물 (2 x 4.5 mL)로 세척하고, 질소 하에서 건조시켜 거의 백색인 분말로서 표제 화합물을 산출하였다 (8.86 g (부정확한 수율 91.7%)). 3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in dichloromethane (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3- in a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, the products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Then water (9 mL) was added dropwise. Additional dichloromethane (18 mL) was added to stir the thick suspension and the mixture was stirred at 0 ° C. for 1 h. The mixture was filtered and the solid washed with ice cold 2: 1 dichloromethane-water (2 x 4.5 mL) and dried under nitrogen to yield the title compound as an almost white powder (8.86 g (incorrect yield 91.7%). )).
실시예 13 Example 13
프로피오니트릴Propionitrile 중의 3- 3-of 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )카르보닐]) Carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
프로피오니트릴 (18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (즉,실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 3-피콜린 (5.06 mL, 4.84 g, 52 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 0 내지 5℃에서 1시간 동안, 이어서 실온에서 3시간 동안 교반하였다. 이어서 물 (9 mL)을 적가하고, 혼합물을 실온에서 1시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 3:1 프로피오니트릴-물 (2 x 4 mL)로, 이어서 프로피오니트릴 (2 x 4 mL)로 세척하고, 질소 하에서 건조시켜 거의 백색인 분말로서 표제 화합물을 산출하였다 (9.37 g (부정확한 수율 97.0%)). 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in propionitrile (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) ) In a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie the product of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 1 hour and then at room temperature for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at rt for 1 h. The mixture is filtered and the solid is washed with 3: 1 propionitrile-water (2 x 4 mL) followed by propionitrile (2 x 4 mL) and dried under nitrogen to yield the title compound as an almost white powder. (9.37 g (incorrect yield 97.0%)).
실시예 14Example 14
메틸methyl 에틸 케톤 중의 3- 3- in ethyl ketone 브로모Bromo -N-[4--N- [4- 클로로Chloro -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )카르보닐]) Carbonyl] 페닐Phenyl ]-1-(3-] -1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-1H-) -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
메틸 에틸 케톤 (MEK, 18 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (6.05 g, 20.0 mmol) 및 2-아미노-5-클로로-N,3-디메틸벤자미드 (실시예 1, 3, 4 및 5의 생성물) (4.17 g, 21.0 mmol)의 혼합물에 3-피콜린 (5.06 mL, 4.84 g, 52 mmol)을 첨가하였다. 혼합물을 -5℃로 냉각한 후, 메탄술포닐 클로라이드 (1.86 mL, 2.75 g, 24 mmol)를 -5 내지 0℃에서 적가하였다. 혼합물을 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 물 (9 mL)을 적가하고, 혼합물을 실온에서 1시간 동안 교반하였다. 혼합물을 여과하고, 고형물을 3:1 MEK-물 (2 x 4 mL)로, 이어서 MEK (2 x 4 mL)로 세척하고, 질소 하에서 건조시켜 거의 백색인 분말로서 표제 화합물을 산출하였다 (9.27 g (부정확한 수율 95.9%)).3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in methyl ethyl ketone (MEK, 18 mL) (PCT Patent Publication WO 03/015519 for the preparation) 3) to a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at rt for 1 h. The mixture was filtered, the solid was washed with 3: 1 MEK-water (2 × 4 mL), then MEK (2 × 4 mL) and dried under nitrogen to yield the title compound as an almost white powder (9.27 g). (Incorrect yield 95.9%)).
실시예 15Example 15
3-3- 브로모Bromo -1-(3--1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-N-[4-) -N- [4- 시아노Cyano -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )- 카르보닐]) -Carbonyl] 페닐Phenyl ]-1H-] -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (120 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 95.4%, 15.85 g, 50.0 mmol) 및 2-아미노-5-시아노-N,3-디메틸벤자미드 (즉, 실시예 6의 생성물) (9.93 g, 52.5 mmol)의 혼합물에 3-피콜린 (17.5 mL, 16.7 g, 180 mmol)을 첨가하였다. 혼합물을 -10℃로 냉각한 후, 메탄술포닐 클로라이드의 용액 (5.4 mL, 8.0 g, 70 mmol)을 -10 내지 -5℃에서 적가하였다. 혼합물을 이 온도에서 5분 동안, 이어서 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 물 (55 mL)을 적가하였다. 혼합물을 15분 동안 교반한 후, 진한 염산 (5.0 mL, 60 mmol)을 적가하고, 혼합물을 0 내지 5℃에서 1시간 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 2:1 아세토니트릴-물 (2 x 10 mL)로, 이어서 아세토니트릴 (2 x 10 mL)로 세척하고, 질소 하에서 건조시켜 회백색 분말로서 표제 화합물을 산출하였다 (24.70 g (부정확한 수율 99.5%)). m.p. 177-181℃ (분해됨).3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3-p into a mixture of (purity 95.4%, 15.85 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie, the product of Example 6) (9.93 g, 52.5 mmol) Choline (17.5 mL, 16.7 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 3 hours. Water (55 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred at 0-5 ° C. for 1 hour. The mixture was then filtered and the solid was washed with 2: 1 acetonitrile-water (2 x 10 mL), then with acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (24.70). g (incorrect yield 99.5%)). m.p. 177-181 ° C. (decomposed).
1-프로판올 (50 mL)로부터 조 생성물 (5.00 g)을 결정화시켜 백색 결정으로서 표제 화합물을 산출하였다 (4.44 g (회수율 88.8%)). m.p. 217-219℃Crude product (5.00 g) was crystallized from 1-propanol (50 mL) to yield the title compound as white crystals (4.44 g (88.8% recovery)). m.p. 217-219 ℃
실시예 16Example 16
염기로서 피리딘을 사용하는 3-3- using pyridine as base 브로모Bromo -1-(3--1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-N-[4-) -N- [4- 시아노Cyano -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )-카르보닐]) -Carbonyl] 페닐Phenyl ]-1H-] -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (120 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 95.4%, 15.85 g, 50.0 mmol) 및 2-아미노-5-시아노-N,3-디메틸벤자미드 (실시예 6의 생성물) (9.93 g, 52.5 mmol)의 혼합물에 피리딘 (14.6 mL, 14.3 g, 180 mmol)을 첨가하였다. 혼합물을 -10℃로 냉각한 후, 메탄술포닐 클로라이드의 용액 (5.4 mL, 8.0 g, 70 mmol)을 -10 내지 -5℃에서 적가하였다. 혼합물을 이 온도에서 5분 동안, 이어서 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 혼합물을 실온으로 가온하고, 물 (85 mL)을 적가하였다. 혼합물을 15분 동안 교반한 후, 진한 염산 (5.0 mL, 60 mmol)을 적가하고, 혼합물을 1시간 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 4:3 아세토니트릴-물 (2 x 10 mL), 이어서 아세토니트릴 (2 x 10 mL)로 세척하고, 질소 하에서 건조시켜 회백색 분말로서 표제 화합물을 산출하였다 (24.29 g (부정확한 수율 97.9%)). 3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) Pyridine (14.6 mL, in a mixture of 95.4% purity, 15.85 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (product of Example 6) (9.93 g, 52.5 mmol) 14.3 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 3 hours. The mixture was then warmed to rt and water (85 mL) was added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred for 1 hour. The mixture was then filtered, the solid was washed with 4: 3 acetonitrile-water (2 x 10 mL), then acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (24.29 g (Incorrect yield 97.9%)).
실시예 17Example 17
염기로서 2-피콜린을 사용하는 3-3- using 2-picolin as base 브로모Bromo -1-(3--1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-N-[4-시아노-2-) -N- [4-cyano-2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )-카르보닐]) -Carbonyl] 페닐Phenyl ]-1H-] -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (120 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 96.7%, 15.64 g, 50.0 mmol) 및 2-아미노-5-시아노-N,3-디메틸벤자미드 (즉, 실시예 6의 생성물) (9.93 g, 52.5 mmol)의 혼합물에 2-피콜린 (17.8 mL, 16.8 g, 180 mmol)을 첨가하였다. 혼합물을 -10℃로 냉각한 후, 메탄술포닐 클로라이드의 용액 (5.4 mL, 8.0 g, 70 mmol)을 -10 내지 -5℃에서 적가하였다. 혼합물을 이 온도에서 5분 동안, 이어서 0 내지 5℃에서 3시간 동안, 이어서 실온에서 18시간 동안 교반하였다. 이어서 물 (25 mL)을 적가하였다. 혼합물을 15분 동안 교반한 후, 진한 염산 (5.0 mL, 60 mmol)을 적가하고, 혼합물을 1시간 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 4:1 아세토니트릴-물 (2 x 10 mL), 이어서 아세토니트릴 (2 x 10 mL)로 세척하고, 질소 하에서 건조시켜 회백색 분말로서 표제 화합물을 산출하였다 (22.52 g (부정확한 수율 92.0%)).3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 2-ply in a mixture of (purity 96.7%, 15.64 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie, the product of Example 6) (9.93 g, 52.5 mmol) Choline (17.8 mL, 16.8 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes, then at 0-5 ° C. for 3 hours, then at room temperature for 18 hours. Water (25 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred for 1 hour. The mixture was then filtered and the solid was washed with 4: 1 acetonitrile-water (2 x 10 mL), then acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (22.52 g (Inaccurate yield 92.0%)).
실시예 18Example 18
염기로서 2,6-2,6- as base 루티딘을Lutidine 사용하는 3- 3- used 브로모Bromo -1-(3--1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-N-[4-) -N- [4- 시아노Cyano -2--2- 메틸methyl -6-[(-6-[( 메틸아미노Methylamino )-카르보닐]) -Carbonyl] 페닐Phenyl ]-1H-] -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세토니트릴 (120 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 97.6%, 15.50 g, 50.0 mmol) 및 2-아미노-5-시아노-N,3-디메틸벤자미드 (즉, 실시예 6의 생성물) (9.93 g, 52.5 mmol)의 혼합물에 2,6-루티딘 (21.0 mL, 19.3 g, 180 mmol)을 첨가하였다. 혼합물을 -10℃로 냉각한 후, 메탄술포닐 클로라이드의 용액 (5.4 mL, 8.0 g, 70 mmol)을 -10 내지 -5℃에서 적가하였다. 혼합물을 이 온도에서 5분 동안, 이어서 0 내지 5℃에서 1시간 동안, 이어서 실온에서 1시간 동안 교반하였다. 반응물의 NMR 분석은 표제 화합물이 거의 존재하지 않지만, 10.3%의 고리화 유도체가 형성되었음을 나타내었다. 추가의 2,6-루티딘 (11.7 mL, 10.8 g, 100 mmol) 및 메탄술포닐 클로라이드 (3.9 mL, 5.8 g, 50 mmol)를 첨가하고 혼합물을 실온에서 22시간 동안 교반하였다. 반응물의 분석은 9.6%의 표제 화합물 및 89.8%의 고리화 유도체가 형성되었음을 나타내었다. 물 (55 mL)을 적가하였다. 혼합물을 15분 동안 교반한 후, 진한 염산 (5.0 mL, 60 mmol)을 적가하고, 혼합물을 1시간 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 2:1 아세토니트릴-물 (2 x 10 mL)로, 이어서 아세토니트릴 (2 x 10 mL)로 세척하고, 질소 하에서 건조시 켜 밝은 황색 분말을 산출하였다 (21.92 g). 이 고형물을 아세토니트릴 (60 mL) 중에 현탁시키고, 물 (10 mL) 및 염산 (1 N, 10 mL)을 첨가하고, 혼합물을 실온에서 30분 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 3:1 아세토니트릴-물 (2 x 10 mL)로, 이어서 아세토니트릴 (2 x 10 mL)로 세척하고, 진공 오븐에서 건조시켜 회백색 분말로서 표제 화합물을 산출하였다 (20.72 g (부정확한 수율 85.4%)).3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 2,6 in a mixture of (purity 97.6%, 15.50 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie the product of Example 6) (9.93 g, 52.5 mmol) -Lutidine (21.0 mL, 19.3 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes, then at 0-5 ° C. for 1 hour and then at room temperature for 1 hour. NMR analysis of the reaction showed little to no title compound, but 10.3% of the cyclized derivative was formed. Additional 2,6-lutidine (11.7 mL, 10.8 g, 100 mmol) and methanesulfonyl chloride (3.9 mL, 5.8 g, 50 mmol) were added and the mixture was stirred at rt for 22 h. Analysis of the reactants indicated that 9.6% of the title compound and 89.8% of cyclized derivatives were formed. Water (55 mL) was added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred for 1 hour. The mixture was then filtered, the solid was washed with 2: 1 acetonitrile-water (2 x 10 mL) and then with acetonitrile (2 x 10 mL) and dried under nitrogen to yield a light yellow powder (21.92 g ). This solid was suspended in acetonitrile (60 mL), water (10 mL) and hydrochloric acid (1 N, 10 mL) were added and the mixture was stirred at rt for 30 min. The mixture was then filtered, the solid was washed with 3: 1 acetonitrile-water (2 x 10 mL) and then with acetonitrile (2 x 10 mL) and dried in a vacuum oven to yield the title compound as an off-white powder ( 20.72 g (incorrect yield 85.4%)).
실시예 19 Example 19
아세톤 중의 3-3- in acetone 브로모Bromo -1-(3--1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-N-[4-) -N- [4- 시아노Cyano -2--2- 메틸methyl -6-[(메틸아미노)-카르보닐]-6-[(methylamino) -carbonyl] 페닐Phenyl ]-1H-] -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
아세톤 (120 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 97.6%, 15.50 g, 50.0 mmol) 및 2-아미노-5-시아노-N,3-디메틸벤자미드 (즉, 실시예 6의 생성물) (9.93 g, 52.5 mmol)의 혼합물에 3-피콜린 (17.5 mL, 16.7 g, 180 mmol)을 첨가하였다. 혼합물을 -10℃로 냉각한 후, 메탄술포닐 클로라이드의 용액 (5.4 mL, 8.0 g, 70 mmol)을 -10 내지 -5℃에서 적가하였다. 혼합물을 이 온도에서 5분 동안, 이어서 0 내지 5℃에서 3시간 동안 교반하였다. 이어서 물 (55 mL)을 적가하였다. 혼합물을 15분 동안 교반한 후, 진한 염산 (5.0 mL, 60 mmol)을 적가하고, 혼합물을 0 내지 5℃에서 1시간 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 2:1 아세톤-물 (3 x 10 mL)로 세척하고, 질소 하에서 건조시켜 회백색 분말로서 표제 화합물을 산출하였다 (24.07 g (부정확한 수율 99.2%)). 이 고형물의 칼 피셔 (Karl Fisher) 적정 (KFT)은 그것에 5.5 중량%의 물이 함유되어 있음을 나타내었다. 고형물의 일부 (23.35 g)를 진공 오븐에서 건조시켜서 회백색 분말로서 표제 화합물을 산출하였다 (22.16 g, KFT의 측정 결과 0.76 중량%의 물 함유).3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetone (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) ( 3-picoline in a mixture of 97.6% purity, 15.50 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie, the product of Example 6) (9.93 g, 52.5 mmol) (17.5 mL, 16.7 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 3 hours. Water (55 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred at 0-5 ° C. for 1 hour. The mixture was then filtered and the solid was washed with 2: 1 acetone-water (3 × 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (24.07 g (incorrect yield 99.2%)). Karl Fisher titration (KFT) of this solid showed that it contained 5.5% by weight of water. A portion of the solid (23.35 g) was dried in a vacuum oven to yield the title compound as an off-white powder (22.16 g, containing 0.76 wt.% Water as measured by KFT).
실시예 20Example 20
프로피오니트릴Propionitrile 중의 3- 3-of 브로모Bromo -1-(3--1- (3- 클로로Chloro -2--2- 피리디닐Pyridinyl )-N-[4-) -N- [4- 시아노Cyano -2-메틸-6-[(-2-methyl-6-[( 메틸아미노Methylamino )-카르보닐]) -Carbonyl] 페닐Phenyl ]-1H-] -1H- 피라졸Pyrazole -5--5- 카르복사미드의Carboxamide 제조 Produce
프로피오니트릴 (120 mL) 중의 3-브로모-1-(3-클로로-2-피리디닐)-1H-피라졸-5-카르복실산 (제조를 위해 PCT 특허 공개 제WO 03/015519호 참고) (순도 97.6%, 15.50 g, 50.0 mmol) 및 2-아미노-5-시아노-N,3-디메틸벤자미드 (실시예 6의 생성물) (9.93 g, 52.5 mmol)의 혼합물에 3-피콜린 (17.5 mL, 16.7 g, 180 mmol)을 첨가하였다. 혼합물을 -10℃로 냉각한 후, 메탄술포닐 클로라이드의 용액 (5.4 mL, 8.0 g, 70 mmol)을 -10 내지 -5℃에서 적가하였다. 혼합물을 이 온도에서 5분 동안, 이어서 0 내지 5℃에서 4시간 동안 교반하였다. 이어서 물 (55 mL)을 적가하였다. 혼합물을 15분 동안 교반한 후, 진한 염산 (5.0 mL, 60 mmol)을 적가하고, 혼합물을 0 내지 5℃에서 1시간 동안 교반하였다. 이어서 혼합물을 여과하고, 고형물을 2:1 프로피오니트릴-물 (2 x 10 mL)로, 이어서 프로피오니트릴 (2 x 10 mL)로 세척하고, 질소 하에서 건조시켜 회백색 고체로서 표제 화합물을 산출하였다 (21.85 g (부정확한 수율 90.1%)). 이 고형물의 칼 피셔 적정 (KFT)은 그것에 5.4 중량%의 물이 함유되어 있음을 나타내었다. 고형물의 일부 (21.03 g)를 진공 오븐에서 건조시켜서 회백색 분말로서 표제 화합물을 산출하였다 (20.07 g, KFT의 측정 결과 0.9 중량%의 물 함유).3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in propionitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3-picoline in a mixture of) (purity 97.6%, 15.50 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (product of Example 6) (9.93 g, 52.5 mmol) (17.5 mL, 16.7 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 4 hours. Water (55 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred at 0-5 ° C. for 1 hour. The mixture was then filtered and the solid was washed with 2: 1 propionitrile-water (2 × 10 mL) followed by propionitrile (2 × 10 mL) and dried under nitrogen to yield the title compound as an off-white solid. (21.85 g (incorrect yield 90.1%)). The Karl Fischer titration (KFT) of this solid showed that it contained 5.4% by weight of water. A portion of the solid (21.03 g) was dried in a vacuum oven to yield the title compound as off-white powder (20.07 g, containing 0.9 wt.% Water as measured by KFT).
하기 약어를 하기 표에서 사용하였다. The following abbreviations are used in the table below.
t는 3급을 의미하고, s는 2급을 의미하고, n은 노르말을 의미하고, i는 이소를 의미하고, Me는 메틸을 의미하고, Et는 에틸을 의미하고, Pr은 프로필을 의미하고, i-Pr은 이소프로필을 의미하고, Bu는 부틸을 의미한다. 당업계에 공지된 방법과 함께 본원에 기재한 절차에 의해서, 하기 표 1의 화합물을 제조할 수 있고 본 발명의 방법에서 사용할 수 있다. t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, , i -Pr means isopropyl, Bu means butyl. By the procedures described herein together with methods known in the art, the compounds of Table 1 can be prepared and used in the methods of the present invention.
표 2에 본 발명의 방법에 따라서 화학식 1의 화합물을 제조하기 위한 특정 전환을 예시하였다.Table 2 illustrates certain conversions for preparing compounds of Formula 1 according to the methods of the present invention.
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